Substituted piperazines

ABSTRACT

Compounds are provided that act as potent antagonists of the CCR1 receptor, and which have been further confirmed in animal testing for inflammation, one of the hallmark disease states for CCR1. The compounds are generally aryl piperazine derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of Provisional Application Ser. No.60/453,711, filed Jun. 12, 2002, (originally U.S. Ser. No. 10/171,398,filed Jun. 12, 2002) the contents of which is incorporated herein byreference.

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK.

NOT APPLICABLE

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH OR DEVELOPMENT

This application was supported in part by DARPA Grant No.N65236-99-1-5420. The government of the United States may have certainrights in this application.

BACKGROUND OF THE INVENTION

The present invention provides compounds, pharmaceutical compositionscontaining one or more of those compounds or their pharmaceuticallyacceptable salts, which are effective in inhibiting the binding ofvarious chemokines, such as MIP-1α, leukotactin, MPIF-1 and RANTES, tothe CCR1 receptor. As antagonists or modulators for the CCR1 receptor,the compounds and compositions have utility in treating inflammatory andimmune disorder conditions and diseases.

Human health depends on the body's ability to detect and destroy foreignpathogens that might otherwise take valuable resources from theindividual and/or induce illness. The immune system, which comprisesleukocytes (white blood cells (WBCs): T and B lymphocytes, monocytes,macrophages granulocytes, NK cell, mast cells, dendritic cell, andimmune derived cells (for example, osteoclasts)), lymphoid tissues andlymphoid vessels, is the body's defense system. To combat infection,white blood cells circulate throughout the body to detect pathogens.Once a pathogen is detected, innate immune cells and cytotoxic T cellsin particular are recruited to the infection site to destroy thepathogen. Chemokines act as molecular beacons for the recruitment andactivation of immune cells, such as lymphocytes, monocytes andgranulocytes, identifying sites where pathogens exist.

Despite the immune system's regulation of pathogens, certaininappropriate chemokine signaling can develop and has been attributed totriggering or sustaining inflammatory disorders, such as rheumatoidarthritis, multiple sclerosis and others. For example, in rheumatoidarthritis, unregulated chemokine accumulation in bone joints attractsand activates infiltrating macrophages and T-cells. The activities ofthese cells induce synovial cell proliferation that leads, at least inpart, to inflammation and eventual bone and cartilage loss (see,DeVries, M. E., et al., Semin Immunol 11(2):95–104 (1999)). A hallmarkof some demyelinating diseases such as multiple sclerosis is thechemokine-mediated monocyte/macrophage and T cell recruitment to thecentral nervous system (see, Kennedy, et al., J. Clin. Immunol.19(5):273–279 (1999)). Chemokine recruitment of destructive WBCs totransplants has been implicated in their subsequent rejection. See,DeVries, M. E., et al., ibid. Because chemokines play pivotal roles ininflammation and lymphocyte development, the ability to specificallymanipulate their activity has enormous impact on ameliorating andhalting diseases that currently have no satisfactory treatment. Inaddition, transplant rejection may be minimized without the generalizedand complicating effects of costly immunosuppressive pharmaceuticals.

Chemokines, a group of greater than 40 small peptides (7–10 kD), ligatereceptors expressed primarily on WBCs or immune derived cells, andsignal through G-protein-coupled signaling cascades to mediate theirchemoattractant and chemostimulant functions. Receptors may bind morethan one ligand; for example, the receptor CCR1 ligates RANTES(regulated on activation normal T cell expressed), MIP-1α (macrophageinflammatory protein), MPIF-1/CKβ8, and Leukotactin chemokines (amongothers with lesser affinities). To date, 24 chemokine receptors areknown. The sheer number of chemokines, multiple ligand bindingreceptors, and different receptor profiles on immune cells allow fortightly controlled and specific immune responses. See, Rossi, et al.,Ann. Rev. Immunol. 18(1):217–242 (2000). Chemokine activity can becontrolled through the modulation of their corresponding receptors,treating related inflammatory and immunological diseases and enablingorgan and tissue transplants.

The receptor CCR1 and its chemokine ligands, including, for exampleMIP-1α, MPIF-1/CKβ8, leukotactin and RANTES, represent significanttherapeutic targets (see Saeki, et al., Current Pharmaceutical Design9:1201–1208 (2003)) since they have been implicated in rheumatoidarthritis, transplant rejection (see, DeVries, M. E., et al., ibid.),and multiple sclerosis (see, Fischer, et al., J Neuroimmunol.110(1–2):195–208 (2000); Izikson, et al., J. Exp. Med. 192(7):1075–1080(2000); and Rottman, et al., Eur. J. Immunol. 30(8):2372–2377 (2000). Infact, function-blocking antibodies, modified chemokine receptor ligandsand small organic compounds have been discovered, some of which havebeen successfully demonstrated to prevent or treat somechemokine-mediated diseases (reviewed in Rossi, et al., ibid.). Notably,in an experimental model of rheumatoid arthritis, disease development isdiminished when a signaling-blocking, modified-RANTES ligand isadministered (see Plater-Zyberk, et al., Immunol Lett. 57(1–3):117–120(1997)). While function-blocking antibody and small peptide therapiesare promising, they suffer from the perils of degradation, extremelyshort half-lives once administered, and prohibitive expense to developand manufacture, characteristic of most proteins. Small organiccompounds are preferable since they often have longer half lives invivo, require fewer doses to be effective, can often be administeredorally, and are consequently less expensive. Some organic antagonists ofCCR1 have been previously described (see, Hesselgesser, et al., J. Biol.Chem. 273(25):15687–15692 (1998); Ng, et al., J. Med. Chem.42(22):4680–4694 (1999); Liang, et al., J. Biol. Chem.275(25):19000–19008 (2000); and Liang, et al., Eur. J. Pharmacol.389(1):41–49 (2000)). In view of the effectiveness demonstrated fortreatment of disease in animal models (see, Liang, et al., J. Biol.Chem. 275(25):19000–19008 (2000)), the search has continued to identifyadditional compounds that can be used in the treatment of diseasesmediated by CCR1 signaling.

BRIEF SUMMARY OF THE INVENTION

The present invention provides compounds having the formula:

or a pharmaceutically acceptable salt thereof. In the formula above, thesubscript n represents an integer of from 1 to 2, preferably 1. Thesubscript m represents an integer of from 0 to 10, limited by the numberof available substituents positions on the piperazine or homopiperazinering to which it is attached. For example, piperazine derivatives (nis 1) can have from 0 to 8 R groups, preferably 0 to 4 R¹ groups, andmore preferably 0, 1 or 2 R¹ groups. Each R¹ is a substituentindependently selected from C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,C₂₋₈ alkenyl and C₂₋₈ alkynyl, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),—NR^(a)COR^(b), —SO₂R^(a), —X¹COR^(a), —X¹CO₂R^(a), —X¹CONR^(a)R^(b),—X¹NR^(a)COR^(b), —X¹SO₂R^(a), —X¹SO₂NR^(a)R^(b), —X¹NR^(a)R^(b),—X¹OR^(a), wherein X¹ is a member selected from the group consisting ofC₁₋₄ alkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene and each R^(a) andR^(b) is independently selected from the group consisting of hydrogen,C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₃₋₆ cycloalkyl, and wherein thealiphatic portions of each of said R¹ substituents is optionallysubstituted with from one to three members selected from the groupconsisting of OH, O(C₁₋₈ alkyl), SH, S(C₁₋₈ alkyl), CN, NO₂, NH₂,NH(C₁₋₈ alkyl) and N(C₁₋₈ alkyl)₂.

The symbol Ar¹ represents an optionally substituted aryl or heteroarylgroup. Preferred aryl groups are phenyl and naphthyl. Preferredheteroaryl groups are those having from 5 to 10 ring vertices, at leastone of which is a nitrogen atom (e.g., pyridyl, pyridazinyl, pyrazinyl,pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, purinyl and the like).Each of the Ar¹ rings is optionally substituted with from one to five R²substituents independently selected from halogen, —OR^(c), —OC(O)R^(c),—NR^(c)R^(d), —SR^(c), —R^(e), —CN, —NO₂, —CO₂R^(c), —CONR^(c)R^(d),—C(O)R^(c), —OC(O)NR^(c)R^(d), —NR^(d)C(O)R^(c), —NR^(d)C(O)₂R^(e),—NR^(c)—C(O)NR^(c)R^(d), —NH—C(NH₂)═NH, —NR^(e)C(NH₂)═NH,—NH—C(N₂)═NR^(e), —NH—C(NHR^(e))═NH, —S(O)R^(e), —S(O)₂R^(e),—NR^(c)S(O)₂R^(e), —S(O)₂NR^(c)R^(d), —N₃, —X²OR^(c), —X²OC(O)R^(c),—X²NR^(c)R^(d), —X²SR^(c), —X²CN, —X²NO₂, —X²CO₂R^(c), —X²CONR^(c)R^(d),—X²C(O)R^(c), —X²OC(O)NR^(c)R^(d), —X²NR^(d)C(O)R^(c),—X²NR^(d)C(O)₂R^(e), —X²NR^(c)C(O)NR^(c)R^(d), —X²NH—C(NH₂)═NH,—X²NR^(e)C(NH₂)═NH, —X²NH—C(NH₂)═NR^(e), —X²NH—C(NHR^(e))═NH,—X²S(O)R^(e), —X²S(O)₂R^(e), —X²NR^(c)S(O)₂R^(e), —X²S(O)₂NR^(c)R^(d)and —X²N₃, wherein X² is a member selected from the group consisting ofC₁₋₄ alkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene and each R^(c) andR^(d) is independently selected from hydrogen, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,heteroaryl, aryl-C₁-₄ alkyl, and aryloxy-C₁-₄ alkyl, and each R^(e) isindependently selected from the group consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,heteroaryl, aryl-C₁-₄ alkyl, and aryloxy-C₁-₄ alkyl, and each of R^(c),R^(d) and R^(e) is optionally further substituted with from one to threemembers selected from the group consisting of OH, O(C₁₋₈ alkyl), SH,S(C₁₋₈ alkyl), CN, NO₂, NH₂, NH(C₁₋₈ alkyl) and N(C₁₋₈ alkyl)₂.

The symbol HAr represents an optionally substituted heteroaryl group.The heteroaryl groups for HAr can be the same or different from any ofthe heteroaryl groups used for Ar¹. Generally, the HAr groups aremonocyclic, but can also be fused bicyclic systems having from 5 to 10ring atoms, at least one of which is a nitrogen atom. Certain preferredheteroaryl groups are 5 or 6-membered rings having at least one nitrogenatom as a ring vertex and fused ring systems having a 5-membered ringfused to a benzene ring, for example pyrazolyl, imidazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxathiadiazolyl,pyrrolyl, thiazolyl, isothiazolyl, benzimidazolyl, benzopyrazolyl andbenzotriazolyl, each of which is substituted with from one to five R³substituents independently selected from the group consisting ofhalogen, phenyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl,pyridizinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, —OR^(f), —OC(O)R^(f),—NR^(f)R^(g), —SR^(f), —R^(h), —CN, —NO₂, —CO₂R^(f), —CONR^(f)R^(g),—C(O)R^(f), —OC(O)NR^(f)R^(g), —NR^(g)C(O)R^(f), —NR^(g)C(O)₂R^(h),—NR^(f)—C(O)NR^(f)R^(g), —NH—C(NH₂)═NH, —NR^(h)C(NH₂)═NH,—NH—C(NH₂)═NR^(h), —NH—C(NHR^(h))═NH, —S(O)R^(h), —S(O)₂R^(h),—NR^(f)S(O)₂R^(h), —S(O)₂NR^(f)R^(g), —NR^(f)S(O)₂R^(h),—NR^(f)S(O)₂NR^(f)R^(g), —N₃, —X³OR^(f), —X³OC(O)R^(f), —X³NR^(f)R^(g),—X³SR^(f), —X³CN, —X³NO₂, —X³CO₂R^(f), —X³CONR^(f)R^(g), —X³C(O)R^(f),—X³OC(O)NR^(f)R^(g), —X³NR^(g)C(O)R^(f), —X³NR^(g)C(O)₂R^(h),—X³NR^(f)—C(O)NR^(f)R^(g), —X³NH—C(NH₂)═NH, —X³NR^(h)C(NH₂)═NH,—X³NH—C(NH₂)═NR^(h), —X³NH—C(NHR^(h))═NH, —X³S(O)R^(h), —X³S(O)₂R^(h),—X³NR^(f)S(O)₂R^(h), —X³S(O)₂NR^(f)R^(g) and —X³N₃ wherein X³ isselected from the group consisting of C₁₋₄ alkylene, C₂₋₄ alkenylene andC₂₋₄ alkynylene and each R^(f) and R^(g) is independently selected fromhydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, aryl, heteroaryl, aryl-C₁-₄ alkyl, and aryloxy-C₁-₄ alkyl,and each R^(h) is independently selected from the group consisting ofC₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, heteroaryl, aryl-C₁-₄ alkyl, and aryloxy-C₁₋₄ alkyl, and thealiphatic portions of R^(f), R^(g) and R^(h) are optionally furthersubstituted with from one to three members selected from the groupconsisting of OH, O(C₁₋₈ alkyl), SH, S(C₁₋₈ alkyl), CN, NO₂, NH₂,NH(C₁₋₈ alkyl) and N(C₁₋₈ alkyl)₂ and wherein any phenyl, thienyl,furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl,tetrazolyl or oxadiazolyl R³ groups present are optionally substitutedwith from one to three substitutents selected from the group consistingof halogen, —OR^(f), —NR^(f)R^(g), —R^(h), —CN, —NO₂, —CO₂R^(f),—CONR^(f)R^(g), —C(O)R^(f), —X³OR^(f), —X³NR^(f)R^(g),—X³NR^(f)S(O)₂R^(h) and —X³S(O)₂NR^(f)R^(g). Among the most preferredHAr groups are substituted or unsubstituted pyrazoles and substituted orunsubstituted benzopyrazoles. Preferably, substituted or unsubstitutedpyrazoles are attached to the remainder of the molecule via a nitrogenatom of the pyrazole ring. For those embodiments in which HAr is abenzopyrazole ring, attachment to the remainder of the molecule ispreferably via a nitrogen on the pyrazole portion of the fused ringsystem.

The symbol L¹ represents a linking group having from one to three mainchain atoms selected from the group consisting of C, N, O and S andbeing optionally substituted with from one to three substituentsselected from the group consisting of halogen, phenyl, —OR^(i),—OC(O)R^(i), —NR^(i)R^(j), —SR^(i), —R^(k), —CN, —NO₂, —CO₂R^(i),—CONR^(i)R^(j), —C(O)R^(i), —OC(O)NR^(i)R^(j), —NR^(j)C(O)R^(i),—NR^(j)C(O)₂R^(k), —X⁴OR^(i), —X⁴OC(O)R^(i), —X⁴NR^(i)R^(j), —X⁴SR^(i),—X⁴CN, —X⁴NO₂, —X⁴CO₂R^(i), —X⁴CONR^(i)R^(j), —X⁴C(O)R^(i),—X⁴OC(O)NR^(i)R^(j), —X⁴NR^(j)C(O)R^(i) and —X⁴NR^(j)C(O)₂R^(k), whereinX⁴ is selected from the group consisting of C₁₋₄ alkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene and each R^(i) and R^(j) is independentlyselected from hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, heteroaryl, aryl-C₁-₄ alkyl, andaryloxy-C₁-₄ alkyl, and each R^(k) is independently selected from thegroup consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, aryl, heteroaryl, aryl-C₁-₄ alkyl, andaryloxy-C₁-₄ alkyl. In certain preferred embodiments, the linking groupsare unsubstituted, while in other preferred embodiments, substituentsare present that can increase partitioning into selected solvents orinto selected tissues. For example, addition of a hydroxy group to apropylene linkage will generally provide compounds having more favorablesolubility in water. Preferably, L¹ is selected from —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂O—, —CH₂NH—, —CH₂OCH₂— and —CH₂NHCH₂—.

In addition to the compounds provided herein, the present inventionfurther provides pharmaceutical compositions containing one or more ofthese compounds, as well as methods for the use of these compounds intherapeutic methods, primarily to treat diseases associated with CCR1signalling activity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides selected and preferred Ar¹ groups for compounds offormulae I, II and III.

FIGS. 2 and 3 provide selected and preferred HAr groups for compounds offormulae I, II, III and IV.

FIGS. 4A–4C provide structures of selected commercially availablestarting materials.

FIGS. 5A–5N provide structures of selected and preferred compounds offormula I.

DETAILED DESCRIPTION OF THE INVENTION

I. Abbreviation and Definitions

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical, having the number of carbon atoms designated (i.e. C₁-₈ meansone to eight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers toan unsaturated alkyl group having one or more double bonds. Similarly,the term “alkynyl” refers to an unsaturated alkyl group having one ormore triple bonds. Examples of such unsaturated alkyl groups includevinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “cycloalkyl”refers to hydrocarbon rings having the indicated number of ring atoms(e.g., C₃₋₆cycloalkyl) and being fully saturated or having no more thanone double bond between ring vertices. “Cycloalkyl” is also meant torefer to bicyclic and polycyclic hydrocarbon rings such as, for example,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingfour or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Additionally, for dialkylaminogroups, the alkyl portions can be the same or different and can also becombined to form a 3–7 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(a)R^(b) ismeant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl andthe like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to five heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a heteroatom. Non-limitingexamples of aryl groups include phenyl, naphthyl and biphenyl, whilenon-limiting examples of heteroaryl groups include 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl and heteroarylring systems are selected from the group of acceptable substituentsdescribed below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like).

The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in someembodiments, will include both substituted and unsubstituted forms ofthe indicated radical. Preferred substituents for each type of radicalare provided below. For brevity, the terms aryl and heteroaryl willrefer to substituted or unsubstituted versions as provided below, whilethe term “alkyl” and related aliphatic radicals is meant to refer tounsubstituted version, unless indicated to be substituted.

Substituents for the alkyl radicals (including those groups oftenreferred to as alkylene, alkenyl, alkynyl and cycloalkyl) can be avariety of groups selected from: -halogen, —OR′, —NR′R″, —SR′,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —CN and—NO₂ in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″ and R′″ eachindependently refer to hydrogen, unsubstituted C₁-₈ alkyl, unsubstitutedheteroalkyl, unsubstituted aryl, aryl substituted with 1–3 halogens,unsubstituted C₁-₈ alkyl, C₁-₈ alkoxy or C₁-₈ thioalkoxy groups, orunsubstituted aryl-C₁-₄ alkyl groups. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 3-, 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant toinclude 1-pyrrolidinyl and 4-morpholinyl.

Similarly, substituents for the aryl and heteroaryl groups are variedand are generally selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′,—R′, —CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′,—NR″C(O)₂R′, —NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —N₃,perfluoro(C₁–C₄)alkoxy, and perfluoro(C₁–C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C₁-₄ alkyl, andunsubstituted aryloxy-C₁-₄ alkyl. Other suitable substituents includeeach of the above aryl substituents attached to a ring atom by analkylene tether of from 1–4 carbon atoms.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula-A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—, —NH—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integerof from 1 to 3. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁-₆ alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occuring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1–19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention. The compounds of the present invention may alsocontain unnatural proportions of atomic isotopes at one or more of theatoms that constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

II. General

The present invention derives from the discovery that compounds offormula I (as well as the subgeneric formulae II, III and IV) act aspotent antagonists of the CCR1 receptor. This antagonist activity hasbeen further confirmed in animal testing for inflammation, one of thehallmark disease states for CCR1. Accordingly, the compounds providedherein are useful in pharmaceutical compositions, methods for thetreatment of CCR1-mediated diseases, and as controls in assays for theidentification of competitive CCR1 antagonists.

III. Compounds

In one aspect, the present invention provides compounds having theformula:

or a pharmaceutically acceptable salt thereof.

In the formula above, the subscript n represents an integer of from 1 to2, preferably 1. The subscript m represents an integer of from 0 to 10,limited by the number of available substituents positions on thepiperazine or homopiperazine ring to which it is attached. For example,piperazine derivatives (n is 1) can have from 0 to 8 R¹ groups,preferably 0 to 4 R¹ groups, and more preferably 0, 1 or 2 R¹ groups.

The symbol Ar¹ represents an optionally substituted aryl or heteroarylgroup. Preferred aryl groups are phenyl and naphthyl. Preferredheteroaryl groups are those having from 5 to 10 ring vertices, at leastone of which is a nitrogen atom (e.g., pyridyl, pyridazinyl, pyrazinyl,pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, purinyl and the like).Each of the Ar¹ rings is optionally substituted with from one to five R²substituents independently selected from halogen, —OR^(c), —OC(O)R^(c),—NR^(c)R^(d), —SR^(c), —R^(e), —CN, —NO₂, —CO₂R^(c), —CONR^(c)R^(d),—C(O)R^(c), —OC(O)NR^(c)R^(d), —NR^(d)C(O)R^(c), —NR^(d)C(O)₂R^(e),—NR^(c)—C(O)NR^(c)R^(d), —NH—C(NH₂)═NH, —NR^(e)C(NH₂)═NH,—NH—C(NH₂)═NR^(e), —NH—C(NHR^(e))═NH, —S(O)R^(e), —S(O)₂R^(e),—NR^(c)S(O)₂R^(e), —S(O)₂NR^(c)R^(d), —N₃, —X²OR^(c), —X²OC(O)R^(c),—X²NR^(c)R^(d), —X²SR^(c), —X²CN, —X²NO₂, —X²CO₂R^(c), —X²CONR^(c)R^(d),—X²C(O)R^(c), —X²OC(O)NR^(c)R^(d), —X²NR^(d)C(O)R^(c),—X²NR^(d)C(O)₂R^(e), —X²NR^(c)C(O)NR^(c)R^(d), —X²NH—C(NH₂)═NH,—X²NR^(e)C(NH₂)═NH, —X²NH—C(NH₂)═NR^(e), —X²NH—C(NHR^(e))═NH,—X²S(O)R^(e), —X²S(O)₂R^(e), —X²NR^(c)S(O)₂R^(e), —X²S(O)₂NR^(c)R^(d)and —X²N₃, wherein X² is a member selected from the group consisting ofC₁₋₄ alkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene and each R^(c) andR^(d) is independently selected from hydrogen, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,heteroaryl, aryl-C₁-₄ alkyl, and aryloxy-C₁-₄ alkyl, and each R^(e) isindependently selected from the group consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl,heteroaryl, aryl-C₁-₄ alkyl, and aryloxy-C₁-₄ alkyl, and each of R^(c),R^(d) and R^(e) is optionally further substituted with from one to threemembers selected from the group consisting of OH, O(C₁₋₈ alkyl), SH,S(C₁₋₈ alkyl), CN, NO₂, NH₂, NH(C₁₋₈ alkyl) and N(C₁₋₈ alkyl)₂.

HAr is an optionally substituted heteroaryl group. The heteroaryl groupsfor HAr can be the same or different from any of the heteroaryl groupsused for Ar¹. Generally, the HAr groups are monocyclic, but can also befused bicyclic systems having from 5 to 10 ring atoms, at least one ofwhich is a nitrogen atom. Certain preferred heteroaryl groups are 5 or6-membered rings having at least one nitrogen atom as a ring vertex andfused ring systems having a 5-membered ring fused to a benzene ring, forexample pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, oxathiadiazolyl, pyrrolyl, thiazolyl,isothiazolyl, benzimidazolyl, benzopyrazolyl and benzotriazolyl.Preferably, the fused bicyclic HAr moiety, when present, is attached tothe remainder of the molecule through the 5-member ring. Additionally,each of the HAr groups is substituted with from one to five R³substituents independently selected from the group consisting ofhalogen, phenyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl,pyridizinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, —OR^(f), —OC(O)R^(f),—NR^(f)R^(g), —SR¹, —R^(h), —CN, —NO₂, —CO₂R^(f), —CONR^(f)R^(g),—C(O)R^(f), —OC(O)NR^(f)R^(g), —NR^(g)C(O)R^(f), —NR^(g)C(O)₂R^(h),—NR^(f)—C(O)NR^(f)R^(g), —NH—C(NH₂)═NH, —NR^(h)C(NH₂)═NH,—NH—C(NH₂)═NR^(h), —NH—C(NHR^(h))═NH, —S(O)R^(h), —S(O)₂R^(h),—NR^(f)S(O)₂R^(h), —S(O)₂NR^(f)R^(g), —NR^(f)S(O)₂R^(h),—NR^(f)S(O)₂NR^(f)R^(g), —N₃, —X³OR^(f), —X³OC(O)R^(f), —X³NR^(f)R^(g),—X³SR^(f), —X³CN, —X³NO₂, —X³CO₂R^(f), —X³CONR^(f)R^(g), —X³C(O)R^(f),—X³OC(O)NR^(f)R^(g), —X³NR^(g)C(O)R^(f), —X³NR^(g)C(O)₂R^(h),—X³NR^(f)—C(O)NR^(f)R^(g), —X³NH—C(NH₂)═NH, —X³NR^(h)C(NH₂)═NH,—X³NH—C(NH₂)═NR^(h), —X³NH—C(NHR^(h))═NH, —X³S(O)R^(h), —X³ S(O)₂R^(h),—X³NR^(f)S(O)₂R^(h), —X³S(O)₂NR^(f)R^(g) and —X³N₃ wherein X³ isselected from the group consisting of C₁₋₄ alkylene, C₂₋₄ alkenylene andC₂₋₄ alkynylene and each R^(f) and R^(g) is independently selected fromhydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, aryl, heteroaryl, aryl-C₁-₄ alkyl, and aryloxy-C₁-₄ alkyl,and each R^(h) is independently selected from the group consisting ofC₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, heteroaryl, aryl-C₁-₄ alkyl, and aryloxy-C₁-₄ alkyl, and thealiphatic portions of R^(f), R^(g) and R^(h) are optionally furthersubstituted with from one to three members selected from the groupconsisting of OH, O(C₁₋₈ alkyl), SH, S(C₁₋₈ alkyl), CN, NO₂, NH₂,NH(C₁₋₈ alkyl) and N(C₁₋₈ alkyl)₂ and wherein any phenyl, thienyl,furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl,tetrazolyl, or oxadiazolyl R³ groups present are optionally substitutedwith from one to three substitutents selected from the group consistingof halogen, —OR^(f), —NR^(f)R^(g), —R^(h), —CN, —NO₂, —CO₂R^(f),—CONR^(f)R^(g), —C(O)R^(f), —X³OR^(f), —X³NR^(f)R^(g),—X³NR^(f)S(O)₂R^(h) and —X³S(O)₂NR^(f)R^(g). Among the most preferredHAr groups are substituted or unsubstituted pyrazoles and substituted orunsubstituted benzopyrazoles. Preferably, substituted or unsubstitutedpyrazoles are attached to the remainder of the molecule via a nitrogenatom of the pyrazole ring. For those embodiments in which HAr is abenzopyrazole ring, attachment to the remainder of the molecule ispreferably via a nitrogen on the pyrazole portion of the fused ringsystem.

The symbol L¹ represents a linking group having from one to three mainchain atoms selected from the group consisting of C, N, O and S andbeing optionally substituted with from one to three substituentsselected from the group consisting of halogen, phenyl, —OR^(i),—OC(O)R^(i), —NR^(i)R^(j), —SR^(i), —R^(k), —CN, —NO₂, —CO₂R^(i),—CONR^(i)R^(j), —C(O)R^(i), —OC(O)NR^(i)R^(j), —NR^(j)C(O)R^(i),—NR^(j)C(O)₂R^(k), —X⁴OR^(i), —X⁴OC(O)R^(i), —X⁴NR^(i)R^(j), —X⁴SR^(i),—X⁴CN, —X⁴NO₂, —X⁴CO₂R^(i), —X⁴CONR^(i)R^(j), —X⁴C(O)R^(i),—X⁴OC(O)NR^(i)R^(j), —X⁴NR^(j)C(O)R^(i) and —X⁴NR^(j)C(O)₂R^(k), whereinX⁴ is selected from the group consisting of C₁-₄ alkylene, C₂₋₄alkenylene and C₂₋₄ alkynylene and each R^(i) and R^(j) is independentlyselected from hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, heteroaryl, aryl-C₁₋₄ alkyl, andaryloxy-C₁-₄ alkyl, and each R^(k) is independently selected from thegroup consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, aryl, heteroaryl, aryl-C₁-₄ alkyl, andaryloxy-C₁-₄ alkyl. In certain preferred embodiments, the linking groupsare unsubstituted, while in other preferred embodiments, substituentsare present that can increase partitioning into selected solvents orinto selected tissues. For example, addition of a hydroxy group to apropylene linkage will generally provide compounds having more favorablesolubility in water. Preferably, L¹ is selected from —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂O—, —CH₂NH—, —CH₂OCH₂— and —CH₂NHCH₂—.

Returning to the piperazine or homopiperazine portion of the compounds,each R¹ is a substituent independently selected from C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, —COR^(a),—CO₂R^(a), —CONR^(a)R^(b), —NR^(a)COR^(b), —SO₂R^(a), —X¹COR^(a),—X¹CO₂R^(a), —X¹CONR^(a)R^(b), —X¹NR^(a)COR^(b), —X¹SO₂R^(a),—X¹SO₂NR^(a)R^(b), —X¹NR^(a)R^(b), —X¹OR^(a), wherein X¹ is a memberselected from the group consisting of C₁₋₄ alkylene, C₂₋₄ alkenylene andC₂₋₄ alkynylene and each R^(a) and R^(b) is independently selected fromthe group consisting of hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl and C₃₋₆cycloalkyl, and wherein the aliphatic portions of each of said R¹substituents is optionally substituted with from one to three membersselected from the group consisting of OH, O(C₁₋₈ alkyl), SH, S(C₁₋₈alkyl), CN, NO₂, NH₂, NH(C₁₋₈ alkyl) and N(C₁₋₈ alkyl)₂.

Excluded from the above generic formula, as well as each of the formulaebelow, are those compounds that are either commercially available orknown in the literature, including: CAS Reg. No. 492422-98-7,1-[[4-bromo-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-(5-chloro-2-methylphenyl)-piperazine;CAS Reg. No. 351986-92-0,1-[[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-(4-fluorophenyl)-piperazine;CAS Reg. No. 356039-23-1,1-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)acetyl]-4-(4-fluorophenyl)-piperazine;1-(2-{4-nitro-3,5-dimethyl-1H-pyrazol-1-yl}propanoyl)-4-phenylpiperazine;2-(2,4-Dinitro-imidazol-1-yl)-1-[4-(4-fluorophenyl)-piperazin-1-yl]-ethanone;2-(2,4-Dinitro-imidazol-1-yl)-1-(4-phenyl-piperazin-1-yl)-ethanone;2-(4-Nitro-imidazol-1-yl)-1-(4-phenyl-piperazin-1-yl)-ethanone; and CASReg. No. 492992-15-1,3-[3-Fluoro-4-[4-[(1-pyrazolyl)acetyl]piperazine-1-yl]phenyl]-5-[[(isoxazol-3-yl)amino]methyl]isoxazole.

A number of preferred groups of embodiments can be outlined as follows.

In a first group of preferred embodiments, the compounds are representedby formula I in which Ar¹ is selected from

-   -   (i) phenyl, substituted with from 1 to 5 R² groups;    -   (ii) pyridinyl, substituted with from 1 to 4 R² groups; and    -   (iii) pyrazinyl, substituted with from 1 to 3 R² groups;    -   (iv) pyridazinyl, substituted with from 1 to 3 R² groups; and    -   (v) pyridazinyl, substituted with from 1 to 3 R² groups;        wherein each R² is a member independently selected from the        group consisting of halogen, —OR^(c), —OC(O)R^(c), —NR^(c)R^(d),        —SR^(c), —R^(e), —CN, —NO₂, —CO₂R^(c), —CONR^(c)R^(d),        —C(O)R^(c), —OC(O)NR^(c)R^(d), —NR^(d)C(O)R^(c),        —NR^(d)C(O)₂R^(e), —NR^(c)—C(O)NR^(c)R^(d), —S(O)R^(e),        —S(O)₂R^(e), —NR^(c)S(O)₂R^(e), —S(O)₂NR^(c)R^(d) and —N₃,        wherein each R^(c) and R^(d) is independently selected from        hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈        alkenyl and C₂₋₈ alkynyl, and each R^(e) is independently        selected from the group consisting of C₁₋₈ alkyl, C₁₋₈        haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl,        wherein the aliphatic portions of R^(c), R^(d) and R^(e) are        optionally further substituted with from one to three members        selected from the group consisting of OH, O(C₁₋₈ alkyl), SH,        S(C₁₋₈ alkyl), CN, NO₂, NH₂, NH(C₁₋₈ alkyl) and N(C₁₋₈ alkyl)₂.        More preferably, Ar¹ is phenyl substituted with from 1 to 3 R²        groups. Among the most preferred Ar¹ groups are those        represented by:

wherein Hal is F, Cl or Br and each R is independently C₁₋₆ alkyl orC₃₋₆ cycloalkyl.

Further preferred are those embodiments in which L¹ is —CH₂— and isoptionally substituted with phenyl, —R^(k), —X⁴OR^(i), —X⁴OC(O)R^(i),—X⁴NR^(i)R^(j), —X⁴SR^(i), —X⁴CN or —X⁴NO₂. In still further preferredembodiments, HAr is selected from pyrazolyl, triazolyl and tetrazolyl,each of which is optionally substituted with from one to three R³ groupsindependently selected from halogen, phenyl, thienyl, —OR^(f),—OC(O)R^(f), —NR^(f)R^(g), —SR^(f), —R^(h), —CN, —NO₂, —CO₂R^(f),—CONR^(f)R^(g), —C(O)R^(f), —OC(O)NR^(f)R^(g), —NR^(g)C(O)R^(f),—NR^(g)C(O)₂R^(h), —NR^(f)—C(O)NR^(f)R^(g), —S(O)R^(h), —S(O)₂R^(h),—S(O)₂NR^(f)R^(g), —NR^(f)S(O)₂R^(h), —NR^(f)S(O)₂NR^(f)R^(g), —N₃,—X³OR^(f), —X³OC(O)R^(f), —X³NR^(f)R^(g), —X³SR^(f), —X³CN, —X³NO₂,—X³CO₂R^(f), —X³CONR^(f)R^(g), —X³C(O)R^(f), —X³OC(O)NR^(f)R^(g),—X³NR^(g)C(O)R^(f), —X³NR^(g)C(O)₂R^(h), —X³NR^(f)—C(O)NR^(f)R^(g),—X³S(O)R^(h), —X³S(O)₂R^(h), —X³NR^(f)S(O)₂R^(h), —X³S(O)₂NR^(f)R^(g)and —X³N₃ wherein R^(f) and R^(g) are each independently selected fromthe group consisting of H, C₁₋₈ alkyl and C₁₋₈ haloalkyl, and each R^(h)is independently selected from the group consisting of C₁₋₈ alkyl andC₁₋₈ haloalkyl. In still further preferred embodiments, the subscript nis 1, m is 0, 1 or 2, Ar¹ is phenyl substituted with from one to threeR² groups, HAr is pyrazolyl which is substituted with three R³ groupsand L¹ is —CH₂—. In the most preferred embodiments in this group, Ar¹ isselected from those substituted phenyl moieties provided in FIG. 1.

In a second group of preferred embodiments, the compounds arerepresented by formula I in which Ar¹ is selected from

-   -   (i) phenyl, substituted with from 1 to 5 R² groups;    -   (ii) pyridinyl, substituted with from 1 to 4 R² groups; and    -   (iii) pyrimidinyl, substituted with from 1 to 3 R² groups;    -   (iv) pyrazinyl, substituted with from 1 to 3 R² groups; and    -   (v) pyridazinyl, substituted with from 1 to 3 R² groups;        wherein each R² is a member independently selected from the        group consisting of halogen, —X²OR^(c), —X²OC(O)R^(c),        —X²NR^(c)R^(d), —X²SR^(c), —X²CN, —X²NO₂, —X²CO₂R^(c),        —X²CONR^(c)R^(d), —X²C(O)R^(c), —X²OC(O)NR^(c)R^(d),        —X²NR^(d)C(O)R^(c), —X²NR^(d)C(O)₂R^(e),        —X²NR^(c)C(O)NR^(c)R^(d), —X²S(O)R^(e), —X²S(O)₂R^(e),        —X²NR^(c)S(O)₂R^(e), —X²S(O)₂NR^(c)R^(d) and —X²N₃, wherein each        R^(c) and R^(d) is independently selected from hydrogen, C₁₋₈        alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl and C₂₋₈        alkynyl, and each R^(e) is independently selected from the group        consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈        alkenyl and C₂₋₈ alkynyl.

In a third group of preferred embodiments, the compounds are representedby formula I in which HAr is selected from pyrazolyl, triazolyl,tetrazolyl, benzimidazolyl, benzopyrazolyl and benzotriazolyl, each ofwhich is optionally substituted with from one to five R³ groupsindependently selected from the group consisting of halogen, phenyl,thienyl, —OR^(f), —COR^(f), —CO₂R^(f), —CONR^(f)R^(g), —NO₂, —R^(h),—CN, —SR^(f), —S(O)R^(h), —S(O)₂R^(h) and —NR^(f)R^(g), wherein R^(f)and R^(g) are each independently selected from the group consisting ofH, C₁₋₈ alkyl, C₃₋₆ cycloalkyl and C₁₋₈ haloalkyl, and each R^(h) isindependently selected from the group consisting of C₁₋₈ alkyl, C₃₋₆cycloalkyl and C₁₋₈ haloalkyl.

In another group of preferred embodiments, the compounds are representedby formula II:

or a pharmaceutically acceptable salt thereof, wherein each of R^(1a),R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), R^(1g) and R^(1h) represents amember independently selected from the group consisting of H, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl.The remaining groups have the meanings provided above with reference toformula I in their most complete interpretation. Preferably, Ar¹ isselected from phenyl and naphthyl, each of which is optionallysubstituted with from one to five R² substitutents independentlyselected from halogen, —OR^(c), —OC(O)R^(c), —NR^(c)R^(d), —SR^(c),—R^(e), —CN, —NO₂, —CO₂R^(c), —CONR^(c)R^(d), —C(O)R^(c),—OC(O)NR^(c)R^(d), —NR^(d)C(O)R^(c), —NR^(d)C(O)₂R^(e),—NR^(c)—C(O)NR^(c)R^(d), —S(O)R^(e), —S(O)₂R^(e), —NR^(c)S(O)₂R^(e),—S(O)₂NR^(c)R^(d) and —N₃, wherein each R^(c) and R^(d) is independentlyselected from hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each R^(e) is independently selectedfrom the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl. In related preferredembodiments, Ar¹ is selected from phenyl and naphthyl, each of which isoptionally substituted with from one to five R² substitutentsindependently selected from halogen, —X²OR^(c), —X²OC(O)R^(c),—X²NR^(c)R^(d), —X²SR^(c), —X²CN, —X²NO₂, —X²CO₂R^(c), —X²CONR^(c)R^(d),—X²C(O)R^(c), —X²OC(O)NR^(c)R^(d), —X²NR^(d)C(O)R^(c),—X²NR^(d)C(O)₂R^(e), —X²NR^(c)C(O)NR^(c)R^(d), —X²S(O)R^(e),—X²S(O)₂R^(e), —X² NR^(c)S(O)₂R^(e), —X²S(O)₂NR^(c)R^(d) and —X²N₃,wherein each R^(c) and R^(d) is independently selected from hydrogen,C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl and C₂₋₈alkynyl, and each R^(e) is independently selected from the groupconsisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyland C₂₋₈ alkynyl. Still more preferably, L¹ is a member selected fromthe group consisting of —CH₂—, —CH₂CH₂—, —CH₂O— and —CH₂NH—, each ofwhich is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₄alkyl,C₁₋₄haloalkyl and phenyl. In still further preferred embodiments, HAr isselected from pyrazolyl, triazolyl, tetrazolyl and benzopyrazolyl, eachof which is optionally substituted with from one to five R³ groupsindependently selected from halogen, phenyl, thienyl, —OR^(f),—OC(O)R^(f), —NR^(f)R^(g), —SR^(f), —R^(h), —CN, —NO₂, —CO₂R^(f),—CONR^(f)R^(g), —C(O)R^(f), —OC(O)NR^(f)R^(g), —NR^(g)C(O)R^(f),—NR^(g)C(O)₂R^(h), —NR^(f)—C(O)NR^(f)R^(g), —S(O)R^(h), —S(O)₂R^(h),—NR^(f)S(O)₂R^(h), —S(O)₂NR^(f)R^(g), —NR^(f)S(O)₂R^(h),—NR^(f)S(O)₂NR^(f)R^(g), —X³OR^(f), —X³OC(O)R^(f), —X³NR^(f)R^(g),—X³SR^(f), —X³CN, —X³NO₂, —X³CO₂R^(f), —X³CONR^(f)R^(g), —X³C(O)R^(f),—X³OC(O)NR^(f)R^(g), —X³NR^(g)C(O)R^(f), —X³NR^(g)C(O)₂R^(h),—X³NR^(f)—C(O)NR^(f)R^(g), —X³S(O)R^(h), —X³S(O)₂R^(h),—X³NR^(f)S(O)₂R^(h) and —X³S(O)₂NR^(f)R^(g) wherein X³ is selected fromthe group consisting of C₁₋₄ alkylene, C₂₋₄ alkenylene and C₂₋₄alkynylene and each R^(f) and R^(g) is independently selected fromhydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl andC₂₋₈ alkynyl, and each R^(h) is independently selected from the groupconsisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, and wherein any phenyl or thienyl group present isoptionally substituted with from one to three substitutents selectedfrom the group consisting of halogen, —OR^(f), —NR^(f)R^(g), —R^(h),—CN, —NO₂, —CO₂R^(f), —CONR^(f)R^(g), —C(O)R^(f), —X³OR^(f),—X³NR^(f)R^(g), —X³NR^(f)S(O)₂R^(h) and —X³ S(O)₂NR^(f)R^(g). Still morepreferably, HAr is pyrazolyl or benzopyrazolyl, each of which isoptionally substituted with from one to three R³groups independentlyselected from halogen, phenyl, thienyl, —OR^(f), —CO₂R^(f), —COR^(f),—CONR^(f)R^(g), —NO₂, —R^(h), —CN, —SR^(f), —S(O)R^(h), —S(O)₂R^(h) and—NR^(f)R^(g), wherein each R^(f) and R^(g) is independently selectedfrom H, C₁₋₈ alkyl and C₁₋₈ haloalkyl, and each R^(h) is independentlyselected from C₁₋₈ alkyl and C₁₋₈ haloalkyl. Most preferably, HAr isselected from the substituted pyrazolyl moieties provided in FIGS. 2 and3.

In a related group of preferred embodiments, the compound is representby formula II, above, wherein Ar¹ is phenyl, optionally substituted withfrom one to five R² substitutents independently selected from the groupconsisting of halogen, —OR^(c), —OC(O)R^(c), —NR^(c)R^(d), —SR^(c),—R^(e), —CN, —NO₂, —CO₂R^(c), —CONR^(c)R^(d), —C(O)R^(c),—OC(O)NR^(c)R^(d), —NR^(d)C(O)R^(c), —NR^(d)C(O)₂R^(e),NR^(c)—C(O)NR^(c)R^(d), —S(O)R^(e), —S(O)₂R^(e), —S(O)₂NR^(c)R^(d) and—N₃, wherein each R^(c) and R^(d) is independently selected fromhydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl, andC₂₋₈ alkynyl, and each R^(e) is independently selected from the groupconsisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyland C₂₋₈ alkynyl, wherein the alkyl portions of the substituents areoptionally substituted with one or two hydroxy or amino groups; L¹ is—CH₂—; HAr is pyrazolyl or benzopyrazolyl, each of which is optionallysubstituted with from one to three R³ groups independently selected fromthe group consisting of halogen, phenyl, thienyl, OR^(f), CO₂R^(f),CONR^(f)R^(g), NO₂, R^(h), CN, SR^(f), S(O)R^(h), S(O)₂R^(h) andNR^(f)R^(g), wherein each R^(f) and R^(g) is independently selected fromthe group consisting of H, C₁₋₈ alkyl and C₁₋₈ haloalkyl, and each Rh isindependently selected from the group consisting of C₁₋₈ alkyl and C₁₋₈haloalkyl; and each of R^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(1f),R^(1g) and R^(1h) are members independently selected from the groupconsisting of H, C₁₋₄ alkyl and C₁₋₄ haloalkyl, wherein at least six ofR^(1a) through R^(1h) are H.

In yet another group of preferred embodiments, compounds are providedhaving formula III:

or a pharmaceutically acceptable salt thereof, wherein the subscript mis an integer of from 0 to 2; each R¹ is selected from C₁₋₄ alkyl andC₁₋₄ haloalkyl; R^(2a), R^(2b), R^(2c), R^(2d) and R^(2e) are eachmembers independently selected from hydrogen, halogen, —OR^(c),—OC(O)R^(c), —NR^(c)R^(d), —SR^(c), —R^(e), —CN, —NO₂, —CO₂R^(c),—CONR^(c)R^(d), —C(O)R^(c), —OC(O)NR^(c)R^(d), —NR^(d)C(O)R^(c),—NR^(d)C(O)₂R^(e), —NR^(c)—C(O)NR^(c)R^(d), —S(O)R^(e), —S(O)₂R^(e),—NR^(c)S(O)₂R^(e), —S(O)₂NR^(c)R^(d), —N₃, —X²OR^(c), —X²OC(O)R^(c),—X²NR^(c)R^(d), —X²SR^(c), —X²CN, —X²NO₂, —X²CO₂R^(c), —X²CONR^(c)R^(d),—X²C(O)R^(c), —X²OC(O)NR^(c)R^(d), —X²NR^(d)C(O)R^(c),—X²NR^(d)C(O)₂R^(e), —X²NR^(c)C(O)NR^(c)R^(d), —X²S(O)R^(e),—X²S(O)₂R^(e), —X²NR^(c)S(O)₂R^(e), —X²S(O)₂NR^(c)R^(d) and —X²N₃,wherein X² is C₁₋₄ alkylene, and each R^(c) and R^(d) is independentlyselected from hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each R^(e) is independently selectedfrom the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each of R^(c), R^(d) andR^(e) is optionally further substituted with from one to three membersselected from the group consisting of OH, O(C₁₋₈ alkyl), SH, S(C₁₋₈alkyl), CN, NO₂, NH₂, NH(C₁₋₈ alkyl) and N(C₁₋₈ alkyl)₂; R^(3a), R^(3b)and R^(3c) are each members independently selected from hydrogen,halogen, phenyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl,pyridizinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, —OR^(f), —OC(O)R^(f),—NR^(f)R^(g), —SR^(f), —R^(h), —CN, —NO₂, —CO₂R^(f), —CONR^(f)R^(g),—C(O)R^(f), —OC(O)NR^(f)R^(g), —NR^(g)C(O)R^(f), —NR^(g)C(O)₂R^(h),—NR^(f)—C(O)NR^(f)R^(g), —S(O)R^(h), —S(O)₂R^(h), —NR^(f)S(O)₂R^(h),—S(O)₂NR^(f)R^(g), —NR^(f)S(O)₂R^(h), —NR^(f)S(O)₂NR^(f)R^(g),—X³OR^(f), —X³OC(O)R^(f), —X³NR^(f)R^(g), —X³SR^(f), —X³CN, —X³NO₂,—X³CO₂R^(f), —X³CONR^(f)R^(g), —X³C(O)R^(f), —X³OC(O)NR^(f)R^(g),—X³NR^(g)C(O)R^(f), —X³NR^(g)C(O)₂R^(h), —X³NR^(f)—C(O)NR^(f)R^(g),—X³S(O)R^(h), —X³S(O)₂R^(h), —X³NR^(f)S(O)₂R^(h) and —X³S(O)₂NR^(f)R^(g) wherein X³ is C₁₋₄ alkylene, each R^(f) and R^(g) isindependently selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each R^(h) isindependently selected from the group consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and whereinany phenyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl,pyridizinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, triazolyl, tetrazolyl, or oxadiazolyl group present isoptionally substituted with from one to three substitutents selectedfrom the group consisting of halogen, —OR^(f), —NR^(f)R^(g), —R^(h),—CN, —NO₂, —CO₂R^(f), —CONR^(f)R^(g), —C(O)R^(f), —X³OR^(f),—X³NR^(f)R^(g), —X³NR^(f)S(O)₂R^(h) and —X³S(O)₂NR^(f)R^(g).

Within the preferred group of formula III above, certain groups ofembodiments are particularly preferred. In one group of particularlypreferred embodiments, the subscript m is 0 or 1 and at least one ofR^(2a) or R^(2e) is hydrogen. More preferably, at least one of R^(3a),R^(3b) and R^(3c) is selected from halogen and C₁₋₄ haloalkyl. Stillmore preferably, R^(2d) is hydrogen and at least two of R^(3a), R^(3b)and R^(3c) are selected from halogen and C₁₋₄ haloalkyl with theremaining member being other than hydrogen. In related, and preferredembodiments, m is 0 or 1 and at least one of R^(2a) or R^(2e), ishydrogen, R^(2d) is hydrogen, R^(2c) is selected from F, Cl, Br, CN,NO₂, CO₂CH₃, C(O)CH₃ and S(O)₂CH₃, and at least two of R^(3a), R^(3b)and R^(3c) are selected from halogen and C₁₋₄ haloalkyl with theremaining member being other than hydrogen. In another group ofparticularly preferred embodiments, the subscript m is 0 or 1; andR^(2a) and R^(2e) are both hydrogen. More preferably, at least one ofR^(3a), R^(3b) and R^(3c) is selected from halogen and C₁₋₄ haloalkyl.Still more preferably, at least one of R^(3a), R^(3b) and R^(3c) isselected from halogen and C₁₋₄ haloalkyl, and the remaining members ofR^(3a), R^(3b) and R^(3c) are other than hydrogen. In yet another groupof particularly preferred embodiments, the subscript m is 0 or 1; andR^(2b) and R^(2e) are both hydrogen. More preferably, at least one ofR^(3a), R^(3b) and R^(3c) is selected from halogen and C₁₋₄ haloalkyl.Still more preferably, at least one of R^(3a), R^(3b) and R^(3c) isselected from halogen and C₁₋₄ haloalkyl, and the remaining members ofR^(3a), R^(3b) and R^(3c) are other than hydrogen.

Still other preferred groups of formula III above, are:

Turning first to the compounds of formula IIIa, R^(3b) is preferablyhalogen, nitro or cyano, more preferably halogen and most preferablychloro or bromo; R^(3c) is preferably C₁₋₆ alkyl, C₁₋₆ haloalkyl or C₃₋₆cycloalkyl; R^(2c) is halogen and R^(2b) is —OR^(c) or R^(e) whereinR^(c) is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and R^(e) is selected fromthe group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each of R^(c) and R^(e) is optionallyfurther substituted with from one to three members selected from thegroup consisting of OH, O(C₁₋₈ alkyl), SH, S(C₁₋₈ alkyl), CN, NO₂, NH₂,NH(C₁₋₈ alkyl) and N(C₁₋₈ alkyl)₂.

For the compounds of formula IIIb, R^(3b) is preferably halogen, nitroor cyano, more preferably halogen and most preferably chloro or bromo;R^(3a) is preferably C₁₋₆ alkyl, C₁₋₆ haloalkyl or C₃₋₆ cycloalkyl;R^(2c) is preferably halogen and R^(2b) is preferably —OR^(c) or R^(e)wherein R^(c) is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl,C₃₋₆ cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and R^(e) is selectedfrom the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each of R^(c) and R^(e)is optionally further substituted with from one to three membersselected from the group consisting of OH, O(C₁₋₈ alkyl), SH, S(C₁₋₈alkyl), CN, NO₂, NH₂, NH(C₁₋₈ alkyl) and N(C₁₋₈ alkyl)₂.

For the compounds of formula IIIc, R^(3a) is selected from NH₂, CF₃,SCH₃, Ph and thienyl; R^(3b) is chloro or bromo; R^(3c) is preferablyC₁₋₆ alkyl, C₁₋₆ haloalkyl or C₃₋₆ cycloalkyl; R^(2c) is hydrogen,halogen, cyano or nitro; and R^(2b) is selected from hydrogen, halogen,—OR^(c), —OC(O)R^(c), —NR^(c)R^(d), —SR^(c), —R^(e), —CO₂R^(c),—CONR^(c)R^(d), —C(O)R^(c), —S(O)R^(e), —S(O)₂R^(e), —X²OR^(c),—X²OC(O)R^(c), —X²NR^(c)R^(d), —X²SR^(c), —X²CO₂R^(c), —X²CONR^(c)R^(d),—X²C(O)R^(c), —X²OC(O)NR^(c)R^(d), X²NR^(d)(O)R^(c),—X²NR^(d)C(O)₂R^(e), —X²NR^(c)C(O)NR^(c)R^(d), —X²S(O)R^(e),—X²S(O)₂R^(e), —X²NR^(c)S(O)₂R^(e), —X²S(O)₂NR^(c)R^(d) and —X²N₃,wherein X² is C₁₋₄ alkylene, and each R^(c) and R^(d) is independentlyselected from hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each R^(e) is independently selectedfrom the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each of R^(c), R^(d) andR^(e) is optionally further substituted with from one to three membersselected from the group consisting of OH, O(C₁₋₈ alkyl), SH, S(C₁₋₈alkyl), CN, NO₂, NH₂, NH(C₁₋₈ alkyl) and N(C₁₋₈ alkyl)₂. In the mostpreferred embodiments, R^(2c) is halogen, cyano or nitro; R^(2b) isR^(e) or —OR^(c); R^(3a) is selected from the group consisting of NH₂,CF₃, SCH₃, Ph and thienyl; R^(3b) is chloro or bromo; and R^(3c) isselected from the group consisting of C₁₋₆ alkyl and C₃₋₆ cycloalkyl.

In related, and preferred embodiments, compounds of formula IIIc areprovided wherein R^(3c) is selected from NH₂, CF₃, SCH₃, Ph and thienyl;R^(3b) is chloro or bromo; R^(3a) is preferably C₁₋₆ alkyl, C₁₋₆haloalkyl or C₃₋₆ cycloalkyl; R^(2c) is hydrogen, halogen, cyano ornitro, preferably halogen; and R^(2b) is selected from hydrogen,halogen, —OR^(c), —OC(O)R^(c), —NR^(c)R^(d), —SR^(c), —R^(e), —CO₂R^(c),—CONR^(c)R^(d), —C(O)R^(c), —S(O)R^(e), —S(O)₂R^(e), —X²OR^(c),—X²OC(O)R^(c), —X²NR^(c)R^(d), —X²SR^(c), —X²CO₂R^(c), —X²CONR^(c)R^(d),—X²C(O)R^(c), —X²OC(O)NR^(c)R^(d), —X²NR^(d)C(O)R^(c),—X²NR^(d)C(O)₂R^(e), —X²NR^(c)C(O)NR^(c)R^(d), —X²S(O)R^(e),—X²S(O)₂R^(e), —X²NR^(c)S(O)₂R^(e), —X²S(O)₂NR^(c)R_(d) and —X²N₃,wherein X² is C₁₋₄ alkylene, and each R^(c) and R^(d) is independentlyselected from hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl,C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each R^(e) is independently selectedfrom the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each of R^(c), R^(d) andR^(e) is optionally further substituted with from one to three membersselected from the group consisting of OH, O(C₁₋₈ alkyl), SH, S(C₁₋₈alkyl), CN, NO₂, NH₂, NH(C₁₋₈ alkyl) and N(C₁₋₈ alkyl)₂. In the mostpreferred embodiments, R^(2c) is halogen, cyano or nitro; R^(2b) isR^(e) or —OR^(c); R^(3a) is selected from the group consisting of C₁₋₆alkyl and C₃₋₆ cycloalkyl; R^(3c) is selected from the group consistingof NH₂, CF₃, SCH₃, Ph and thienyl; and R^(3b) is chloro or bromo.

For the compounds of formula IIId, R^(3a) is selected from NH₂, CF₃,SCH₃, Ph and thienyl; R^(3b) is chloro or bromo; R^(3c) is preferablyC₁₋₆ alkyl, C₁₋₆ haloalkyl or C₃₋₆ cycloalkyl; R^(2a) is preferablyother than hydrogen, and is selected from halogen, —OR^(c), —OC(O)R^(c),—NR^(c)R^(d), —SR^(c), —R^(e), —CO₂R^(c), —CONR^(c)R^(d), —C(O)R^(c),—S(O)R^(e), —S(O)₂R^(e), —X²OR^(c), —X²OC(O)R^(c), —X²NR^(c)R^(d),—X²SR^(c), —X²CO₂R^(c), —X²CONR^(c)R^(d), —X²C(O)R^(c),—X²OC(O)NR^(c)R^(d), —X²NR^(d)C(O)R^(c), —X²NR^(d)C(O)₂R^(e),—X²NR^(c)C(O)NR^(c)R^(d), —X²S(O)R^(e), —X²S(O)₂R^(e),—X²NR^(c)S(O)₂R^(e), —X²S(O)₂NR^(c)R^(d) and —X²N₃; R^(2c) is hydrogen,halogen, cyano or nitro, preferably halogen; and R^(2d) is selected fromhydrogen, halogen, —OR^(c), —OC(O)R^(c), —NR^(c)R^(d), —SR^(c), —R^(e),—CO₂R^(c), —CONR^(c)R^(d), —C(O)R^(c), —S(O)R^(e), —S(O)₂R^(e),—X²OR^(c), —X²OC(O)R^(c), —X²NR^(c)R^(d), —X²SR^(c), —X²CO₂R^(c),—X²CONR^(c)R^(d), —X²C(O)R^(c), —X²OC(O)NR^(c)R^(d), —X²NR^(d)C(O)R^(c),—X² NR^(d)C(O)₂R^(e), —X²NR^(c)C(O)NR^(c)R^(d), —X²S(O)R^(e),—X²S(O)₂R^(e), —X²NR^(c)S(O)₂R^(e), —X²S(O)₂NR^(c)R^(d) and —X²N₃,wherein each X² is C₁₋₄ alkylene, and each R^(c) and R^(d) isindependently selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each R^(e) isindependently selected from the group consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each ofR^(c), R^(d) and R^(e) is optionally further substituted with from oneto three members selected from the group consisting of OH, O(C₁₋₈alkyl), SH, S(C₁₋₈ alkyl), CN, NO₂, NH₂, NH(C₁₋₈ alkyl) and N(C₁₋₈alkyl)₂; and no more than one of R^(2a) and R^(2d) is hydrogen.Preferably, each of R^(2a) and R^(2d) is other than hydrogen. In themost preferred embodiments, R^(2a) is other than hydrogen; R^(2c) ishalogen, cyano or nitro; R^(2d) is R^(e) or —OR^(c); R^(3a) is selectedfrom the group consisting of C₁₋₆ alkyl and C₃₋₆ cycloalkyl; R^(3b) ischloro or bromo; and R^(3c) is selected from the group consisting ofNH₂, CF₃, SCH₃, Ph and thienyl.

In related and preferred embodiments, compounds of formula IIId areprovided wherein R^(3c) is selected from NH₂, CF₃, SCH₃, Ph and thienyl;R^(3b) is chloro or bromo; R^(3a) is preferably C₁₋₆ alkyl, C₁₋₆haloalkyl or C₃₋₆ cycloalkyl; R^(2a) is hydrogen, halogen, —OR^(c),—OC(O)R^(c), —NR^(c)R^(d), —SR^(c), —R^(e), —CO₂R^(c), —CONR^(c)R^(d),—C(O)R^(c), —S(O)R^(e), —S(O)₂R^(e), —X²OR^(c), —X²OC(O)R^(c),—X²NR^(c)R^(d), —X²SR^(c), —X²CO₂R^(c), —X²CONR^(c)R^(d), —X²C(O)R^(c),—X²OC(O)NR^(c)R^(d), —X²NR^(d)C(O)R^(c), —X²NR^(d)C(O)₂R^(e),—X²NR^(c)C(O)NR^(c)R^(d), —X²S(O)R^(e), —X²S(O)₂R^(e),—X²NR^(c)S(O)₂R^(e), —X²S(O)₂NR^(c)R^(d) and —X²N₃; R^(2c) is hydrogen,halogen, cyano or nitro; and R^(2d) is selected from hydrogen, halogen,—OR^(c), —OC(O)R^(c), —NR^(c)R^(d), —SR^(c), —R^(e), —CO₂R^(c),—CONR^(c)R^(d), —C(O)R^(c), —S(O)R^(e), —S(O)₂R^(e), —X²OR^(c),—X²OC(O)R^(c), —X²NR^(c)R^(d), —X²SR^(c), —X²CO₂R^(c), —X²CONR^(c)R^(d),—X²C(O)R^(c), —X²OC(O)NR^(c)R^(d), —X²NR^(d)C(O)R^(c),—X²NR^(d)C(O)₂R^(e), —X²NR^(c)C(O)NR^(c)R^(d), —X²S(O)R^(e),—X²S(O)₂R^(e), —X²NR^(c)S(O)₂R^(e), —X²S(O)₂NR^(c)R^(d) and —X²N₃,wherein each X² is C₁₋₄ alkylene, and each R^(c) and R^(d) isindependently selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each R^(e) isindependently selected from the group consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each ofR^(c), R^(d) and R^(e) is optionally further substituted with from oneto three members selected from the group consisting of OH, O(C₁₋₈alkyl), SH, S(C₁₋₈ alkyl), CN, NO₂, NH₂, NH(C₁₋₈ alkyl) and N(C₁₋₈alkyl)₂; and no more than one of R^(2a) and R^(2d) is hydrogen.Preferably, each of R^(2a) and R^(2d) is other than hydrogen. In themost preferred embodiments, R^(2a) is other than hydrogen; R^(2c) ishalogen, cyano or nitro; R^(2d) is R^(e) or —OR^(c); R^(3a) is selectedfrom the group consisting of NH₂, CF₃, SCH₃, Ph and thienyl; R^(3b) ischloro or bromo; and R^(3c) is selected from the group consisting ofC₁₋₆ alkyl and C₃₋₆ cycloalkyl.

In yet another group of preferred embodiments, the compounds areselected from formulae IVa–IVe:

wherein R¹ and the subscript m have the meaning provided above forformula III, and each of R^(2a), R^(2b), R^(2c) and R^(2d) aresubstituents independently selected from hydrogen, halogen, —OR^(c),—OC(O)R^(c), —NR^(c)R^(d), —SR^(c), —R^(e), —CN, —NO₂, —CO₂R^(c),—CONR^(c)R^(d), —C(O)R^(c), —OC(O)NR^(c)R^(d), —NR^(d)C(O)R^(c),—NR^(d)C(O)₂R^(e), —NR^(c)—C(O)NR^(c)R^(d), —NH—C(NH₂)═NH,—NR^(e)C(NH₂)═NH, —NH—C(NH₂)═NR^(e), —NH—C(NHR^(e))═NH, —S(O)R^(e),—S(O)₂R^(e), —S(O)₂NR^(c)R^(d), —NR^(c)S(O)₂R^(e),—NR^(c)S(O)₂NR^(c)R^(d), —N₃, —X²OR^(c), —X²OC(O)R^(c), —X²NR^(c)R^(d),—X²SR^(c), —X²CN, —X²NO₂, —X²CO₂R^(c), —X²CONR^(c)R^(d), —X²C(O)R^(c),—X²OC(O)NR^(c)R^(d), —X²NR^(d)C(O)R^(c), —X²NR^(d)C(O)₂R^(e),—X²NR^(c)C(O)NR^(c)R^(d), —X²NH—C(NH₂)═NH, —X²NR^(e)C(NH₂)═NH,—X²NH—C(NH₂)═NR^(e), —X²NH—C(NHR^(e))═NH, —X²S(O)R^(e), —X²S(O)₂R^(e),—X²S(O)₂NR^(c)R^(d), —X²NR^(c)S(O)₂R^(e), —X¹N₃, aryl and heteroaryl,wherein X², R^(c), R^(d) and R^(e) have the meanings provided above withrespect to the compounds of formula I. Similarly, each of R^(3a), R^(3b)and R^(3c) represents a substituent independently selected fromhydrogen, halogen, phenyl, thienyl, furanyl, pyridyl, pyrimidinyl,pyrazinyl, pyridizinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, —OR^(f),—OC(O)R^(f), —NR^(f)R^(g), —SR^(f), —R^(h), —CN, —NO₂, —CO₂R^(f),—CONR^(f)R^(g), —C(O)R^(f), —OC(O)NR^(f)R^(g), —NR^(g)C(O)R^(f),—NR^(g)C(O)₂R^(h), —NR^(f)—C(O)NR^(f)R^(g), —NH—C(NH₂)═NH,—NR^(h)C(NH₂)═NH, —NH—C(NH₂)═NR^(h), —NH—C(NHR^(h))═NH, —S(O)R^(h),—S(O)₂R^(h), —S(O)₂NR^(f)R^(g), —NR^(f)S(O)₂R^(h),—NR^(f)S(O)₂NR^(f)R^(g), —N₃, —X³OR^(f), —X³OC(O)R^(f), —X³NR^(f)R^(g),—X³SR^(f), —X³CN, —X³NO₂, —X³CO₂R^(f), —X³CONR^(f)R^(g), —X³C(O)R^(f),—X³OC(O)NR^(f)R^(g), —X³NR^(g)C(O)R^(f), —X³NR^(g)C(O)₂R^(h),—X³NR^(f)—C(O)NR^(f)R^(g), —X³NH—C(NH₂)═NH, —X³NR^(h)C(NH₂)═NH,—X³NH—C(NH₂)═NR^(h), —X³NH—C(NHR^(h))═NH, —X³S(O)R^(h), —X³S(O)₂R^(h),—X³S(O)₂NR^(f)R^(g), —X³NR^(f)S(O)₂R^(h) and —X³N₃ wherein X³, R^(f),R^(g) and R^(h) have the meaning provided above with respect to thecompounds of formula I, and wherein no more than two of R^(3a), R^(3b)and R^(3c) are hydrogen, preferably, no more than one of R^(3a), R^(3b)and R^(3c) is hydrogen, and still more preferably, each of R^(3a),R^(3b) and R^(3c) is other than hydrogen.

Turning first to the compounds of formula IVa, in one group ofparticularly preferred embodiments, at least one of R^(3a), R^(3b) andR^(3c) is selected from halogen and C₁₋₄ haloalkyl. Still morepreferably, at least one of R^(2b) and R^(2d) is hydrogen and at leasttwo of R^(3a), R^(3b) and R^(3c) are selected from halogen and C₁₋₄haloalkyl. In related, and preferred embodiments, R^(2c) is selectedfrom F, Cl, Br, CN, NO₂, CO₂CH₃, C(O)CH₃ and S(O)₂CH₃, and at least twoof R^(3a), R^(3b) and R^(3c) are selected from halogen and C₁₋₄haloalkyl with the remaining member being other than hydrogen.

Similarly, certain compounds of formula IVb are preferred. Particularlypreferred are those compounds of formula IVb in which at least one ofR^(3a), R^(3b) and R^(3c) is selected from halogen and C₁₋₄ haloalkyl.Still more preferably, at least one of R^(2b) and R^(2d) is hydrogen andat least two of R^(3a), R^(3b) and R^(3c) are selected from halogen andC₁₋₄ haloalkyl. In related, and preferred embodiments, R^(2c) isselected from F, Cl, Br, CN, NO₂, CO₂CH₃, C(O)CH₃ and S(O)₂CH₃, and atleast two of R^(3a), R^(3b) and R^(3c) are selected from halogen andC₁₋₄ haloalkyl with the remaining member being other than hydrogen.

Turning next to the compounds of formula IVc, preferred embodiments arethose in which at least one of R^(2a), R^(2c) and R^(2d), preferablyR^(2c) is selected from F, Cl, Br, CN, NO₂, CO₂CH₃, C(O)CH₃ andS(O)₂CH₃; and at least two of R^(3a), R^(3b) and R^(3c) are selectedfrom halogen and C₁₋₄ haloalkyl with the remaining member being otherthan hydrogen. In other preferred embodiments, one of R^(2c) and R^(2d)is selected from F, Cl, Br, CN, NO₂, CO₂CH₃, C(O)CH₃ and S(O)₂CH₃, andthe other is an aryl or heteroaryl group, for example, phenyl, thienyl,furanyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, and at leasttwo of R^(3a), R^(3b) and R^(3c) are selected from halogen and C₁₋₄haloalkyl with the remaining member being other than hydrogen.

For the compounds of formula IVd, preferred embodiments are those inwhich at least one of R^(2a), R^(2b) and R^(2d) is selected from F, Cl,Br, CN, NO₂, CO₂CH₃, C(O)CH₃ and S(O)₂CH₃, and at least two of R^(3a),R^(3b) and R^(3c) are selected from halogen and C₁₋₄ haloalkyl with theremaining member being other than hydrogen. In other preferredembodiments, one of R^(2b) and R^(2d) is selected from F, Cl, Br, CN,NO₂, CO₂CH₃, C(O)CH₃ and S(O)₂CH₃ and the other is an aryl or heteroarylgroup, for example, phenyl, thienyl, furanyl, oxazolyl, isoxazolyl,thiazolyl and isothiazolyl, and at least two of R^(3a), R^(3b) andR^(3c) are selected from halogen and C₁₋₄ haloalkyl with the remainingmember being other than hydrogen.

For the compounds of formula IVe, preferred embodiments are those inwhich at least one of R^(2a), R^(2b) and R^(2c) is selected from F, Cl,Br, CN, NO₂, CO₂CH₃, C(O)CH₃ and S(O)₂CH₃, and at least two of R^(3a),R^(3b) and R^(3c) are selected from halogen and C₁₋₄ haloalkyl with theremaining member being other than hydrogen. In other preferredembodiments, one of R^(2b) and R^(2c) is selected from F, Cl, Br, CN,NO₂, CO₂CH₃, C(O)CH₃ and S(O)₂CH₃, and the other is an aryl orheteroaryl group, for example, phenyl, thienyl, furanyl, oxazolyl,isoxazolyl, thiazolyl and isothiazolyl, and at least two of R^(3a),R^(3b) and R^(3c) are selected from halogen and C₁₋₄ haloalkyl with theremaining member being other than hydrogen.

In yet another group of preferred embodiments, the compounds areselected from formulae IVf–IVi:

wherein R¹ and the subscript m have the meaning provided above forformula III, and each of R^(2a), R^(2b), R^(2c), R^(2d), R^(3a), R^(3b)and R^(3c) have the meaning provided above for formulae IVa–IVe.Additionally, R^(2e) represents a substituent selected from the groupsprovided for R^(2a) in formulae IVa–IVe above.

In still other embodiments, compounds are provided having formulae Vaand Vb:

wherein each of R¹, the subscript m, R^(2a), R^(2b), R^(2c), R^(2d),R^(3a), R^(3b) and R^(3c) have the meaning provided above for formulaeIVa–IVe.IV. Pharmaceutical Compositions

In addition to the compounds provided above, compositions for modulatingCCR1 activity in humans and animals will typically contain apharmaceutical carrier or diluent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacyand drug delivery. All methods include the step of bringing the activeingredient into association with the carrier which constitutes one ormore accessory ingredients. In general, the pharmaceutical compositionsare prepared by uniformly and intimately bringing the active ingredientinto association with a liquid carrier or a finely divided solid carrieror both, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self emulsifications as described in U.S. patentapplication Ser. No. 20020012680, hard or soft capsules, syrups,elixirs, solutions, buccal patch, oral gel, chewing gum, chewabletablets, effervescent powder and effervescent tablets. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents,antioxidants and preserving agents in order to provide pharmaceuticallyelegant and palatable preparations. Tablets contain the activeingredient in admixture with non-toxic pharmaceutically acceptableexcipients which are suitable for the manufacture of tablets. Theseexcipients may be for example, inert diluents, such as cellulose,silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate,glucose, mannitol, sorbitol, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example PVP, cellulose,PEG, starch, gelatin or acacia, and lubricating agents, for examplemagnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated, enterically or otherwise, by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such asmono-diglycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols. Additionally, the compounds can be administeredvia ocular delivery by means of solutions or ointments. Still further,transdermal delivery of the subject compounds can be accomplished bymeans of iontophoretic patches and the like. For topical use, creams,ointments, jellies, solutions or suspensions, etc., containing thecompounds of the present invention are employed. As used herein, topicalapplication is also meant to include the use of mouth washes andgargles.

V. Methods of Treating Diseases Modulated by CCR1

In yet another aspect, the present invention provides methods oftreating CCR1-mediated conditions or diseases by administering to asubject having such a disease or condition, a therapeutically effectiveamount of a compound of formula I above. The “subject” is defined hereinto include animals such as mammals, including, but not limited to,primates (e.g., humans), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice and the like.

CCR1 provides a target for interfering with or promoting specificaspects of immune cell functions, or more generally, with functionsassociated with CCR1 expression on a wide range of cell types in amammal, such as a human. Compounds that inhibit CCR1, are particularlyuseful for modulating monocyte, macrophage, lymphocyte, granulocyte, NKcell, mast cells, dendritic cell, and certain immune derived cell (forexample, osteoclasts) function for therapeutic purposes. Accordingly,the present invention is directed to compounds which are useful in theprevention and/or treatment of a wide variety of inflammatory andimmunoregulatory disorders and diseases (see Saeki, et al., CurrentPharmaceutical Design 9:1201–1208 (2003)).

For example, an instant compound that inhibits one or more functions ofCCR1 may be administered to inhibit (i.e., reduce or prevent)inflammation or cellular infiltration associated with an immunedisorder. As a result, one or more inflammatory processes, such asleukocyte emigration or infiltration, chemotaxis, exocytosis (e.g., ofenzymes, histamine) or inflammatory mediator release, can be inhibited.For example, monocyte infiltration to an inflammatory site (e.g., anaffected joint in arthritis, or into the CNS in MS) can be inhibitedaccording to the present method.

Similarly, an instant compound that promotes one or more functions ofCCR1 is administered to stimulate (induce or enhance) an inflammatoryresponse, such as leukocyte emigration, chemotaxis, exocytosis (e.g., ofenzymes, histamine) or inflammatory mediator release, resulting in thebeneficial stimulation of inflammatory processes. For example, monocytescan be recruited to combat bacterial infections.

Diseases and conditions associated with inflammation, immune disordersand infection can be treated using the method of the present invention.In a preferred embodiment, the disease or condition is one in which theactions of immune cells such monocyte, macrophage, lymphocyte,granulocyte, NK cell, mast cell, dendritic cell, or certain immunederived cell (for example, osteoclasts) are to be inhibited or promoted,in order to modulate the inflammatory or autoimmune response.

In one group of embodiments, diseases or conditions, including chronicdiseases, of humans or other species can treated with modulators of CCR1function. These diseases or conditions include: (1) allergic diseasessuch as systemic anaphylaxis or hypersensitivity responses, drugallergies, insect sting allergies and food allergies, (2) inflammatorybowel diseases, such as Crohn's disease, ulcerative colitis, ileitis andenteritis, (3) vaginitis, (4) psoriasis and inflammatory dermatoses suchas dermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria and pruritus, (5) vasculitis, (6) spondyloarthropathies, (7)scleroderma, (8) asthma and respiratory allergic diseases such asallergic asthma, allergic rhinitis, hypersensitivity lung diseases andthe like, (9) autoimmune diseases, such as fibromyalagia, scleroderma,ankylosing spondylitis, juvenile RA, Still's disease, polyarticularjuvenile RA, pauciarticular juvenile RA, polymyalgia rheumatica,rheumatoid arthritis, psoriatic arthritis, osteoarthritis, polyarticulararthritis, multiple sclerosis, systemic lupus erythematosus, type Idiabetes, type II diabetes, glomerulonephritis, and the like, (10) graftrejection (including allograft rejection and graft-v-host disease), and(11) other diseases in which undesired inflammatory responses or immunedisorders are to be inhibited, such as cardiovascular disease includingatherosclerosis, myositis, neurodegenerative diseases (e.g., Alzheimer'sdisease), encephalitis, meningitis, hepatitis, nephritis, sepsis,sarcoidosis, allergic conjunctivitis, otitis, chronic obstructivepulmonary disease, sinusitis, Behcet's syndrome and gout and (12) immunemediated food allergies such as Celiac disease.

In another group of embodiments, diseases or conditions can be treatedwith modulators of CCR1 function. Examples of diseases to be treatedwith modulators of CCR1 function include cancers, cardiovasculardiseases, diseases in which angiogenesis or neovascularization play arole (neoplastic diseases, retinopathy and macular degeneration),infectious diseases (viral infections, e.g., HIV infection, andbacterial infections) and immunosuppressive diseases such as organtransplant conditions and skin transplant conditions. The term “organtransplant conditions” is meant to include bone marrow transplantconditions and solid organ (e.g., kidney, liver, lung, heart, pancreasor combination thereof) transplant conditions.

The compounds of the present invention are accordingly useful in theprevention and treatment of a wide variety of inflammatory andimmunoregulatory disorders and diseases.

Depending on the disease to be treated and the subject's condition, thecompounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration.

In the treatment or prevention of conditions which require chemokinereceptor modulation an appropriate dosage level will generally be about0.001 to 100 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.01 to about 25 mg/kg per day; more preferably about 0.05to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05to 0.5 or 0.5 to 5.0 mg/kg per day. For oral administration, thecompositions are preferably provided in the form of tablets containing1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0,10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0,400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, hereditary characteristics, generalhealth, sex and diet of the subject, as well as the mode and time ofadministration, rate of excretion, drug combination, and the severity ofthe particular condition for the subject undergoing therapy.

Diseases and conditions associated with inflammation, immune disorder,infection and cancer can be treated or prevented with the presentcompounds, compositions, and methods.

The compounds and compositions of the present invention can be combinedwith other compounds and compositions having related utilities toprevent and treat the condition or disease of interest, such asinflammatory or autoimmune disorders, conditions and diseases, includinginflammatory bowel disease, rheumatoid arthritis, osteoarthritis,psoriatic arthritis, polyarticular arthritis, multiple sclerosis,allergic diseases, psoriasis, atopic dermatitis and asthma, and thosepathologies noted above.

For example, in the treatment or prevention of inflammation orautimmunity or for example arthritis associated bone loss, the presentcompounds and compositions may be used in conjunction with ananti-inflammatory or analgesic agent such as an opiate agonist, alipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, acyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, aninterleukin inhibitor, such as an interleukin-1 inhibitor, an NMDAantagonist, an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide, a non steroidal anti-inflammatory agent, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, tenidap, and the like.Similarly, the instant compounds and compositions may be administeredwith an analgesic listed above; a potentiator such as caffeine, an H2antagonist (e.g., ranitidine), simethicone, aluminum or magnesiumhydroxide; a decongestant such as phenylephrine, phenylpropanolamine,pseudoephedrine, oxymetazoline, ephinephrine, naphazoline,xylometazoline, propylhexedrine, or levo desoxy ephedrine; anantitussive such as codeine, hydrocodone, caramiphen, carbetapentane, ordextromethorphan; a diuretic; and a sedating or non sedatingantihistamine.

Likewise, compounds and compositions of the present invention may beused in combination with other drugs that are used in the treatment,prevention, suppression or amelioration of the diseases or conditionsfor which compounds and compositions of the present invention areuseful. Such other drugs may be administered, by a route and in anamount commonly used therefor, contemporaneously or sequentially with acompound or composition of the present invention. When a compound orcomposition of the present invention is used contemporaneously with oneor more other drugs, a pharmaceutical composition containing such otherdrugs in addition to the compound or composition of the presentinvention is preferred. Accordingly, the pharmaceutical compositions ofthe present invention include those that also contain one or more otheractive ingredients or therapeutic agents, in addition to a compound orcomposition of the present invention. Examples of other therapeuticagents that may be combined with a compound or composition of thepresent invention, either administered separately or in the samepharmaceutical compositions, include, but are not limited to: (a) VLA-4antagonists, (b) corticosteroids, such as beclomethasone,methylprednisolone, betamethasone, prednisone, prenisolone,dexamethasone, fluticasone, hydrocortisone, budesonide, triamcinolone,salmeterol, salmeterol, salbutamol, formeterol; (c) immunosuppressantssuch as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolirnus(FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506type immunosuppressants, and mycophenolate, e.g., mycophenolate mofetil(CellCept®); (d) antihistamines (H1-histamine antagonists) such asbromopheniramine, chlorpheniramine, dexchloipheniramine, triprolidine,clemastine, diphenhydramine, diphenylpyraline, tripelennamine,hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine,cyproheptadine, antazoline, pheniramine pyrilamine, astemizole,terfenadine, loratadine, cetirizine, fexofenadine,descarboethoxyloratadine, and the like; (e) non steroidal antiasthmatics (e.g., terbutaline, metaproterenol, fenoterol, isoetharine,albuterol, bitolterol and pirbuterol), theophylline, cromolyn sodium,atropine, ipratropium bromide, leukotriene antagonists (e.g.,zafmlukast, montelukast, pranlukast, iralukast, pobilukast andSKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005);(f) non steroidal anti-inflammatory agents (NSAIDs) such as propionicacid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid,carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen,indoprofen, ketoprofen, rniroprofen, naproxen, oxaprozin, pirprofen,pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acidderivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin andzomepirac), fenamic acid derivatives (e.g., flufenamic acid,meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal),oxicams (e.g., isoxicam, piroxicam, sudoxicam and tenoxican),salicylates (e.g., acetyl salicylic acid and sulfasalazine) and thepyrazolones (e.g., apazone, bezpiperylon, feprazone, mofebutazone,oxyphenbutazone and phenylbutazone); (g) cyclooxygenase-2 (COX-2)inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (h)inhibitors of phosphodiesterase type IV (PDE IV); (i) gold compoundssuch as auranofin and aurothioglucose, (j) etanercept (Enbrel®), (k)antibody therapies such as orthoclone (OKT3), daclizumab (Zenapax®),basiliximab (Simulect®) and infliximab (Remicade®), (1) otherantagonists of the chemokine receptors, especially CCR5, CXCR2, CXCR3,CCR2, CCR3, CCR4, CCR7, CX₃CR1 and CXCR6; (m) lubricants or emollientssuch as petrolatum and lanolin, (n) keratolytic agents (e.g.,tazarotene), (o) vitamin D₃ derivatives, e.g., calcipotriene orcalcipotriol (Dovonex®), (p) PUVA, (q) anthralin (Drithrocreme®), (r)etretinate (Tegison®) and isotretinoin and (s) multiple sclerosistherapeutic agents such as interferon P-1β (Betaseron®), interferon(β-1α (Avonex®), azathioprine (Imurek®, Imuran®), glatiramer acetate(Capoxone®), a glucocorticoid (e.g., prednisolone) and cyclophosphamide(t) DMARDS such as methotrexate (u) other compounds such as5-aminosalicylic acid and prodrugs thereof; hydroxychloroquine;D-penicillamine; antimetabolites such as azathioprine, 6-mercaptopurineand methotrexate; DNA synthesis inhibitors such as hydroxyurea andmicrotubule disrupters such as colchicine. The weight ratio of thecompound of the present invention to the second active ingredient may bevaried and will depend upon the effective dose of each ingredient.Generally, an effective dose of each will be used. Thus, for example,when a compound of the present invention is combined with an NSAID theweight ratio of the compound of the present invention to the NSAID willgenerally range from about 1000:1 to about 1:1000, preferably about200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

VI. EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR wererecorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaksare tabulated in the order: multiplicity (s, singlet; d, doublet; t,triplet; q, quartet; m, multiplet) and number of protons. Massspectrometry results are reported as the ratio of mass over charge,followed by the relative abundance of each ion (in parenthesis). Intables, a single m/e value is reported for the M+H (or, as noted, M−H)ion containing the most common atomic isotopes. Isotope patternscorrespond to the expected formula in all cases. Electrospray ionization(ESI) mass spectrometry analysis was conducted on a Hewlett-Packard MSDelectrospray mass spectrometer using the HP1100 HPLC for sampledelivery. Normally the analyte was dissolved in methanol at 0.1 mg/mLand 1 microlitre was infused with the delivery solvent into the massspectrometer, which scanned from 100 to 1500 daltons. All compoundscould be analyzed in the positive ESI mode, using acetonitrile/waterwith 1% formic acid as the delivery solvent. The compounds providedbelow could also be analyzed in the negative ESI mode, using 2 mM NH₄OAcin acetonitrile/water as delivery system.

Compounds within the scope of this invention can be synthesized asdescribed below, using a variety of reactions known to the skilledartisan. A sample of useful routes to both the arylpiperazine subunitsand to the heteroaromatic subunit are provided below. In thedescriptions of the syntheses that follow, some of the arylpiperazineand pyrazole precursors were obtained from commercial sources. Thesecommercial sources include Aldrich Chemical Co., Acros Organics, RyanScientific Incorporated, Oakwood Products Incorporated, LancasterChemicals, Sigma Chemical Co., Lancaster Chemical Co., TCI-America, AlfaAesar, Davos Chemicals, and GFS Chemicals. Some examples of thesecommercially available compounds are shown in the FIGS. 4A–4C. Also,standard chemistries have been employed to link the arylpiperazine andheteroaromatic subunits (whether commercially obtained or prepared bythe methods below) using a suitably optimized linker, such as the acetylunit described in the body of this invention.

One skilled in the art will also recognize that alternative methods maybe employed to synthesize the target compounds of this invention, andthat the approaches described within the body of this document are notexhaustive, but do provide broadly applicable and practical routes tocompounds of interest.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are claimed.

Regioisomerism is a common property in organic chemistry, and isespecially common with regards to certain structural types providedherein. Those skilled in the art will recognize, with respect to thecompounds described herein, that the coupling reactions with theheteroaromatic ring systems can lead to either one of or a mixture ofdetectable regioisomers.

The detailed description of the experimental procedures used tosynthesize key compounds in this text lead to molecules that aredescribed by the physical data identifying them as well as by thestructural depictions associated with them.

Two regioisomers can sometimes exist for certain compounds of theinvention. For example, compounds such as those of formula III can beprepared wherein the pyrazole moiety is linked to the remainder of themolecule via either of the nitrogen atoms in the pyrazole ring. In thesecases, both regioisomeric types have demonstrated biological propertiesand are meant to be within the scope of all the appended claims, whetherexplicitly drawn or not.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

Example 1

The piperazine ring can be formally attached to the terminal aryl unitin a number of ways: by aromatic nuclephilic displacement reactions,metal catalyzed coupling reactions (arylation reactions of secondaryamines), ring expansion, rearrangement and cyclization reactions and thelike. Also, different protection/deprotection strategies can beutilized. Hence, either all or only part of the final moleculararchitecture can be present during the key aryl coupling step. Examplesfor a variety of such aryl coupling strategies are listed below.

Protocol A: Metal Catalysed Arylation Reactions of Secondary Amines

Synthesis of (5-Chloro-2-piperazin-1-yl-phenyl)-phenyl-methanone

Piperazine (3.6 g, 42.5 mmol), Pd(II)acetate (0.007 g, 0.043 mmol),sodium t-butoxide (0.22 g, 2.4 mmol) and BINAP (0.042 g, 0.068 mmol)were stirred at room temperature in 10 mL dry toluene for 15 min.(2-Bromo-5-chloro-phenyl)-phenyl-methanone (0.5 g, 1.7 mmol) in 10 mLdry toluene was then added into the reaction mixture. The reactionmixture was refluxed at 110° C. for 20 hrs, filtered through a celitebed, washed with toluene, concentrated, taken in ethyl acetate andextracted with 1.5 (N) HCl solution three times. The combined aqueouslayers were washed with diethyl ether. The aqueous layer was neutralizedwith 10% aqueous sodium hydroxide solution and then extracted with ethylacetate three times. The combined ethyl acetate layers were washed withwater and saturated brine solution, dried over anhydrous sodium sulfateand concentrated. Purification by flash chromatography (eluted withCHCl3-MeOH) afforded the title compound as product.

Synthesis of 1-(4-Trifluoromethoxy-phenyl)-piperazine

Piperazine (0.588 g, 6.84 mmol), Pd(II)acetate (0.027 g, 0.123 mmol),sodium t-butoxide (0.837 g, 10.06 mmol) and BINAP (0.154 g, 0.286 mmol)were stirred at room temperature in 10 mL dry toluene for 15 min.4-trifluoromethoxy bromo benzene (1.5 g, 6.22 mmol) in 10 mL dry toluenewas added into the reaction mixture. Then the reaction mixture wasrefluxed at 110° C. for 20 hrs. The reaction mixture was filteredthrough a celite bed, washed with toluene, concentrated, ethyl acetateadded and then extracted with 1.5 (N) aqueous HCl solution three times.The combined aqueous layers were washed with diethyl ether. The aqueouslayer was neutralized with 10% aqueous sodium hydroxide solution andthen extracted with ethyl acetate three times. The combined ethylacetate layers were washed with water and saturated brine solution,dried over anhydrous sodium sulfate and concentrated to afford theproduct.

Synthesis of 1-(4-Methanesulfonyl-phenyl)-piperazine

Piperazine (0.98 g, 11.5 mmol), Pd(II)acetate (0.017 g), sodiumt-butoxide (0.37 g, 4.2 mmol) and BINAP (0.049 g) were stirred at roomtemperature in 10 mL dry toluene for 15 min.1-Bromo-4-methanesulfonyl-benzene (0.9 g, 3.8 mmol) in 10 mL dry toluenewas added into the reaction mixture. Then the reaction mixture wasrefluxed at 110° C. for 20 hrs. The reaction mixture was filteredthrough a celite bed and washed with toluene. The toluene wasconcentrated and the reaction mixture was taken in ethyl acetate andextracted with 1.5 (N) HCl solution three times. The combined aqueouslayers were washed with diethyl ether. The aqueous layer was neutralizedwith 10% aqueous sodium hydroxide solution and then extracted with ethylacetate three times. The combined ethyl acetate layers were washed withwater and saturated brine solution, dried over anhydrous sodium sulfate,concentrated and chromatographed (9/1-CHCl3/MeOH) to afford the product.

Synthesis of 1-(4-Chloro-3-methoxy-phenyl)-piperazine

An oven dried glass vial was charged with 5-Bromo-2-chloroanisole (1.0mmol), N-Bocpiperazine (1.2 mmol), NaOtBu (1.4 mmol),tris(dibenzylideneacetone)-dipalladium(0) {Pd₂dba₃} (0.0025 mmol, 0.5mol %) and BINAP (0.0075 mmol), and the vial was then flushed withnitrogen and capped tightly. The mixture was heated to 80° C. overnightand then cooled to room temperature, taken up in ether, filtered andconcentrated. The crude product was purified by flash columnchromatography on silica gel with ethyl acetate to yield4-(4-Chloro-3-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butylester.

This product (ca. 1 mmol) was dissolved in a methylene chloride (10 mL)and the reaction mixture was cooled to 0° C. To the reaction mixture wasadded TFA:CH₂Cl₂ (2:1)(50% overall) slowly and the reaction was allowedto warm to room temperature. When TLC (1:1 Ethyl acetate:hexane)suggested total consumption of starting material, solvent was removedand the oil residue was taken in ethyl acetate (2×25 mL) and washed withsaturated aqueous NaHCO₃. The organic layer was dried by MgSO₄ andsolvent was removed to yield the title compound as a yellow oil, whichsolidified on standing. ¹H NMR (400 MHz, CDCl₃): 7.18–7.22 (d, 1H),6.44–6.48 (d, 1H), 6.36–6.42 (dd, 1H), 4.8 (s, 2H), 6.62–3.8 (m, 4H),3.46–3.6 (m, 4H). ¹³C NMR (400 MHz, CDCl₃): 164, 158.2, 156.4, 148,119.2, 117, 52.8, 52.2, 48.5, 46.2, 42, 40.4.

Similar approaches, using a key Buckwald coupling, were taken for thepreparation of related phenylpiperazines, some examples of which arelisted below.

Synthesis of 1-(4-Chloro-3-isopropoxy-phenyl)-piperazine

1-Bromo-3-isopropoxy-4-chlorobenzene (preparation described elsewhere)was combined with 1.11 g (6 mmol) of 1-Bocpiperazine, 672 mg (7.0 mmol)of sodium tert-butoxide, 93 mg (0.15 mmol) ofrac-2,2′-Bis(diphenylphosphine)-1,1′-binaphthyl, and 45 mg (0.05 mmol)Tris(dibenzylideneacetone)dipalladium (0) in a flask under an N2atmosphere, and the mixture was heated at 85° C. for 3.5 hours. Theresulting residue was partitioned between a 1/1 mixture of ether andethyl acetate and water, and the phases were separated. The ether/ethylacetate phase was diluted with one volume of hexanes, washed twice with0.5M pH=7 phosphate buffer, and once each with 1M NaOH and brine. Thefinal organic phase was dried over Na2SO4, filtered, and concentrated invacuo to an oil. The oil was dissolved in ethyl acetate, 10 mL each of2M HCl in ether and methanol were added, and the product was isolated byfiltration after crystallization. ¹H NMR (D₂O, 400 MHz): 7.23 (d, 1H),6.69 (s, 1H), 6.59 (d, 1H), 4.53 (m, 1H), 3.28 (m, 8H), 1.20 (d, 6H)ppm.

Synthesis of 1-(4-Chloro-3-ethoxy-phenyl)-piperazine

Title compound was obtained following the same procedure as that used toobtain 1-(4-Chloro-3-isopropoxy-phenyl)-piperazine hydrochloride, withthe single modification of adding ethanol in place of isopropanol duringthe ether-forming reaction. ¹H NMR (D₂O, 400 MHz) 7.22 (d, 1H), 6.64 (s,1H), 6.54 (d, 1H), 4.03 (q, 2H), 3.29 (m, 8H), 1.25 (t, 3H) ppm.

Synthesis of 4-Piperazin-1-yl-benzoic acid methyl ester

BINAP (230 mg, 0.37 mmol), Pd(II)acetate (417 mg, 0.186 mmol), tBuONa(1.25 g, 13 mmol), N-boc piperazine (1.9 g, 10.2 mmol) and THF (40 mL)were mixed together and stirred at room temperature for 30 min under anitrogen atmosphere. 4-bromomethyl benzoate (2 g, 9.3 mmol) in THF (10mL) was added to the mixture drop wise and heated at 70° C. for 14 h.Excess THF was then evaporated and extracted with ethyl acetate. Thecrude product was obtained on concentration of the ethyl acetate layerafter washing with brine and drying. Flash chromatography on silica geldone eluting with 8% ethyl acetate in petroleum ether yielded pure N-BOCprotected product. This intermediate (650 mg, 2.01 mmol) was dissolvedin methanol (20 mL) and then HCl saturated ether (7 mL) was added. Themixture was stirred at room temperature for 14 hours and concentrated.The concentrate was washed with petroleum ether to obtain white solidcompound, 4-Piperazin-1-yl-benzoic acid methyl ester.

Synthesis of 1-(2,4-Dichloro-phenyl)-piperazine

BINAP (219 mg), Pd(II)acetate (397 mg, 0.176 mmol), tBuONa (1.19 g, 12.3mmol), piperazine (837 mg, 9.73 mmol) and THF (40 mL) were mixedtogether and stirred at room temperature for 30 min under nitrogenatmosphere. 2,4-dichlorobromobenzene (2 g, 8.84 mmol) in THF (10 mL) wasadded to the mixture drop wise and heated at 70° C. for 14 h. Excess THFwas then evaporated and extracted with ethyl acetate. The crude productwas obtained on concentration of the ethyl acetate layer after washingwith brine and drying. Flash chromatography on silica gel eluting with2% MeOH in CHCl3 gave 1-(2,4-Dichloro-phenyl)-piperazine.

Synthesis of 1-(4-Chloro-phenyl)-3-(R)-methyl-piperazine

A single neck round bottom flask was charged with 1-chloro-4-iodobenzene (1.0 g, 0.0041 mol) and R(−)-2-methylpiperazine (0.5 g, 0.005mol), potassium t-butoxide (0.705 g, 0.0062 mol),tris(benzylideneacetone)dipalladium(0) (0.095 g, 0.0002 mol) and 1,3bis(2,6-diisopropylphenyl)imidazole-2-ylidene) (0.073 g, 0.0001 mol).The flask was evacuated and filled with nitrogen. Dry dioxane (20 mL)was added and stirred at 70° C. overnight. The reaction mixture wasdiluted with dichloromethane and filtered. Crude compound was purifiedby column chromatography. The compound was dissolved in ether and purgedwith HCl gas to yield 1-(4-Chloro-phenyl)-3-methyl-piperazine.

Synthesis of 1-(4-Chloro-2-Fluorophenyl)-piperazine

Piperazine (1.5 g, 17.8 mmol), Pd(II)acetate (0.032 g, 0.143 mmol),sodium t-butoxide (0.688 g, 10.06 mmol) and BINAP (0.18 g, 0.286 mmol)were stirred at room temperature in 10 mL dry toluene for 15 min.1-bromo-4-chloro-2-fluorobenzene (1.5 g, 7.15 mmol) in 10 mL dry toluenewas added into the reaction mixture. Then the reaction mixture wasrefluxed at 110° C. for 20 hrs. The reaction mixture was filteredthrough a celite bed and washed with toluene, then concentrated and thereaction mixture was taken into ethyl acetate and extracted with 1.5 (N)HCl solution three times. The combined aqueous layer was washed withdiethyl ether. The aqueous layer was neutralized with 10% aqueous sodiumhydroxide solution and then extracted with ethyl acetate three times.The combined ethyl acetate layers were washed with water and saturatedbrine solution, dried over anhydrous sodium sulfate, and concentrated toafford the product as a white solid.

Further Examples of Arylpiperazines Synthesized by Metal CatalysedArylation Methods (Protocol A).

Many other arylpiperazine derivatives were prepared in addition to thespecific experimental examples listed above using similar Palladiummediated coupling methodologies. Examples are listed below.

Protocol B: Piperidine Ring Formation via Cyclization Reactions

Synthesis of 1-(3,4-Difluoro-phenyl)-piperazine

3,4-Difluoro-aniline (1 g, 7.7 mmol) was dissolved in dry n-butanol (10mL) and dry sodium carbonate (3.2 g, 30 mmol) was added to it and thereaction mixture stirred for 1 hour under nitrogen. Bis(2-chloroethyl)amine hydrochloride (1.38 g, 7.7 mmol) in nBuOH (10 mL) were then addedto the mixture via a syringe. The reaction was then heated at 120° C.for 48 h. The nBuOH was evaporated in vacuo and the residue wasextracted with ethyl acetate. Drying of the organic layer with Na₂SO₄followed by concentration afforded the crude product. Purification usingflash column chromatography (chloroform/methanol) afforded1-(3,4-Difluoro-phenyl)-piperazine as an off white solid.

Synthesis of 1-(4-bromo-phenyl)-piperazine

4-Bromo-aniline (2 g, 1.162 mmol) was taken in dry nBuOH (25 mL) and drypotassium carbonate (4.8 g, 34.8 mmol) was added to it and stirred at rtfor 1 h under nitrogen. Bis-(2-chloroethyl) amine hydrochloride 2 (2.49g, 13.9 mmol) in nBuOH (10 mL) was then added to the mixture through asyringe. The reaction mass was then heated at 100° C. for 12 h. nBuOHwas evaporated in vacuo and the residue was extracted with ethylacetate. Drying of the organic layer with Na₂SO₄ followed byconcentration afforded the crude product that on purification silica gelcolumn (chloroform/methanol) afforded the title compound.

Protocol C: Piperidine Ring Formation via a Ring Opening/RingCyclization Strategy

Synthesis of3-[2-(5-Methoxy-2-methyl-phenylamino)-ethyl]-oxazolidin-2-one

To a flask was added 2.95 g (10.3 mmol) of Toluene-4-sulfonic acid,2-(2-oxo-oxazolidin-3-yl)-ethyl ester, 1.56 g (11.4 mmol) of2-methyl-5-methoxyaniline, 2.58 g (18.7 mmol) of potassium carbonate,and 22 mL of anhydrous dimethylformamide, and the mixture was heated at100° C. for seven hours. The reaction was allowed to cool to roomtemperature, and was partitioned between ethyl acetate and water. Thephases were separated, and the ethyl acetate phase was washed withbrine, dried over Na2SO4, filtered, and concentrated to an oil. The oilwas purified by chromatography (120 mL silica, 60 ethyl acetate/40hexanes) to give the corresponding product as a clear oil thatsolidified upon drying: ¹H NMR (DMSO-d6, 400 MHz) 6.81 (d, 1H), 6.11 (s,1H), 6.04 (d, 1H), 4.92 (t, 1H), 4.21 (t, 2H), 3.65 (s, 3H), 3.59 (m,2H), 3.31 (m, 2H), 3.23 (m, 2H), 1.95 (s, 3H) ppm.

Synthesis of 1-(5-Methoxy-2-methyl-phenyl)-piperazine

To 505 mg (2.0 mmol) of3-[2-(5-Methoxy-2-methyl-phenylamino)-ethyl]-oxazolidin-2-one in a flaskwas added 2 mL of 48% HBr in acetic acid, 1 mL of acetic acid, and 1 mLof anisole, and the mixture was heated at 90° C. for six hours. Thesolution was allowed to cool to room tempterature, and 5 mL of CH2Cl2was added. The product crystallized and was isolated by filtration. Thesolids were dissolved in 55 mL of ethanol, 201 mg (2 mmol) oftriethylamine were added, and the solution was heated at reflux for 3hours. The solution was then concentrated in vacuo to give a residuethat was partitioned between ether and water. The phases were separated,and the aqueous phase as basified with 1M NaOH. The aqueous phase wasthen extracted twice with ethyl acetate. The combined ethyl acetatephases were washed once with brine, dried over Na2SO4, filtered, andacidified with 2M HCl in ether. The product was isolated via filtration.

Addition of Various Piperazines to Aryl Halides and Heteroaryl Halidesvia Aryl-halogen Displacement Methodologies

A direct halogen displacement strategy, with thermal assistance ifnecessary, can be complimentary to the metal mediated approaches,discussed above, for the construction of the ring systems providedherein.

Synthesis of 4-Piperazin-1-yl-benzoic acid ethyl ester

To 4-bromobenzoic acid (25 g) and ethanol (1000 mL) was addedconc.sulfuric acid (20 g) drop wise. The reaction mixture was heated at85° C. overnight. The reaction was cooled and ethanol was removed bydistillation and the reaction mixture quenched with water and extractedwith ethyl acetate. The extract was washed with 10% sodium bicarbonate,water, brine and then concentrated to yield the crude ester.4-bromoethyl benzoate (10.0 g, 0.0437 mol) was taken into 250 mL of dryDMF, piperazine (37 g, 0.437 mol) was added, followed by 30 g (0.2185mol) of dry potassium carbonate, 1.0 g of TBAI and 1.5 g of potassiumiodide. The reaction mixture was heated at 135° C. for over night. Thereaction mixture was quenched with water and extracted with ethylacetate. The extracts were washed with water, then brine and thenconcentrated to yield 4-Piperazin-1-yl-benzoic acid ethyl ester as anoff-white solid.

Synthesis of 1-(4-Methoxy-pyridin-2-yl)-piperazine

To 756 mg (5.29 mmol) of 2-Chloro-4-methoxypyridine and 2.27 g (26 mmol)of piperazine in a pressure flask was added 2.7 mL dimethylformamide,and the mixture was heated at 115° C. for 5 hours. The solution wasallowed to cool before opening the flask, and the resulting slurry waspartitioned between ethyl acetate and water. The phases were separated,and the aqueous phase was back-extracted once with ethyl acetate. Thecombined ethyl acetate phases were washed once with brine, dried overNa2SO4, filtered, and the filtrate was acidified with 2M HCl in ether.The product crystallized over night, and the solids were isolated byfiltration to yield product as a white solid: ¹H NMR (D₂O, 400 MHz) 7.72(d, 1H), 6.61 (d, 1H), 6.48 (s, 1H), 3.88 (s, 3H), 3.79 (m, 4H), 3.36(m, 4H) ppm.

Synthesis of 1-(3-Methoxy-pyridin-2-yl)-piperazine

To 966 mg (6.7 mmol) of 2-Chloro-6-methoxypyridine and 2.90 g (34 mmol)of piperazine in a pressure flask was added 3.3 mL dimethylformamide,and the mixture was heated at 115° C. for 5 hours. The solution wasallowed to cool before opening the flask, and the resulting slurry waspartitioned between ethyl acetate and water. The phases were separated,and the aqueous phase was back-extracted once with ethyl acetate. Thecombined ethyl acetate phases were washed once with brine, dried overNa2SO4, filtered, and the filtrate was acidified with 2M HCl in ether.The product crystallized overnight, and was isolated by filtration togive a white solid: ¹H NMR (D₂O, 400 MHz) 7.73 (t, 1H), 6.52 (d, 1H),6.31 (d, 1H), 3.81 (s, 3H), 3.68 (m, 4H), 3.26 (m, 4H) ppm.

Protocol D: Synthesis and Addition of Elaborated Piperazines to Aryl andHeteroaryl Halides via Aryl-halogen Displacement Methodologies

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-piperazin-1-yl-ethanone

To a solution of 1.69 g (9.1 mmol) Boc-piperazine, 2.0 g (8.3 mmol) of(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid, and 1.12g (8.3 mmol) of 1-Hydroxybenzotriazole in 20 mL of dimethylformamide at0° C. was added 1.73 g (9.1 mmol) of1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Thereaction was allowed to stir and warm to room temperature over night,then was partitioned between ether and water. The phases were separated,and the ether phase was washed once each with 1M HCl, water, 1M NaOH,and brine. The ether phase was then dried over Na2SO4, filtered, andconcentrated to a residue.

This crude residue was dissolved in 20 mL ether and 8 mL ethyl acetate,and 20 mL of 5M HCl in isopropanol was added. After 1 hour the mixturewas placed in the freezer over night. The product was isolated byfiltration to give a white solid. ¹H NMR (DMSO-d6, 400 MHz) 9.21 (br s,2H), 5.38 (s, 2H), 3.69 (m, 4H), 3.32 (m, 4H), 2.20 (s, 3H) ppm.

Alternative Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-piperazin-1-yl-ethanone

(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (1.5 g,6.18 mmol) was taken in dry DCM (20 mL) and cooled to 0° C. To this coldmixture was added N-boc piperazine (1.15 g, 6.18 mmol) followed byaddition of T3P (8 g, 12.4 mmol, 50% solution in EtOAc). The reactionwas left overnight at rt. The mixture was diluted with CH2Cl2, washedwith NaHCO3 soln, brine, dried (Na2SO4) and concentrated to afford thecrude product that was washed thoroughly with ether-pet ether to afford4-[2-(4-Chloro-5methyl-3-trifluoromethyl-pyrazol-1yl)-acetyl]-piperazine-1carboxylicacid tert-butyl ester (1.2 g, 2.9 mmol). This was dissolved in methanol(25 mL) cooled to 0° C. and HCl saturated ether (3 mL) was added to it.The mixture was stirred at room temperature for 4 h and concentrated.Crystallization from MeOH/Petroleum ether yielded product.

Synthesis of1-[4-(5-Bromo-pyrimidin-2-yl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone(Protocol D)

To 86 mg (0.25 mmol) of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-piperazine-1-yl-ethanonehydrochloride, 76 mg (0.6 mmol) potassium carbonate, and 48 mg (0.3mmol) of 5-Bromo-2-chloropyrimidine in a vial was added 0.7 mL anhydrousdimethylformamide, and the mixture was heated at 120° C. for 12 hours.The reaction was allowed to cool to room temperature, and waspartitioned between ethyl acetate and water. The phases were separated,and the aqueous phase was back-extracted once with ethyl acetate. Thecombined ethyl acetate phases were washed once each with water, 0.5MpH=7 phosphate buffer, water, 1M NaOH, and brine. The ethyl acetatephase was dried over ‘Na2SO4, filtered, and acidified with 2M HCl inether to precipitate the product as a powder: ¹H NMR (DMSO-d6, 400 MHz)8.48 (s, 2H), 5.37 (s, 2H), 3.81 (m, 2H), 3.72 (m, 2H), 3.57 (m, 4H),2.18 (s, 3H) ppm; MS (ES) M+H expected=467.0, found 466.9.

Additional Compounds of the Invention Prepared by the Aryl-halogenDisplacement Method

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(7H-purin-6-yl)piperazin1-yl]-ethanone

Title compound was prepared following protocol D, wherein 6-Chloropurinewas used as the heteroaryl halide component: ¹H NMR (DMSO-d6, 400 MHz)8.23 (s, 1H), 8.14 (s, 1H), 5.39 (s, 2H), 4.32 (br, 2H), 4.22 (br, 2H),3.60 (m, 4H), 2.19 (s, 3H) ppm; MS (ES) expect M+H=429.1, found 429.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-quinolin-2-yl-piperazin-1-yl)ethanone

Title Compound was prepared following protocol D, wherein2-Chloroquinoline was used as the heteroaryl halide component: ¹H NMR(DMSO-d6, 400 MHz) 8.44 (d, 1H), 8.29 (br, 1H), 7.91 (d, 1H), 7.77 (t,1H), 7.57 (d, 1H), 7.48 (t, 1H), 5.44 (s, 2H), 4.14 (br, 2H), 4.01 (br,2H), 3.78 (br, 2H), 3.70 (br, 2H), 2.20 (s, 3H) ppm; MS (ES) expectM+H=438.1, found 438.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(5-chloro-pyridin-2-yl)-piperazin-1-yl]-ethanone

Title compound was prepared following protocol D, wherein2,5-Dichloropyridine was used as the heteroaryl halide component: MS(ES) expect M+H=422.1, found=422.0; HPLC retention time=4.75 minutes(Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a 4.5 minutegradient of 20% to 95% B with a 1.1 minute wash at 95% B (A=0.1% formicacid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9%acetonitrile).

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethanone

Title compound was prepared following protocol D, wherein2-Chloropyrazine was used as the heteroaryl halide component: ¹H NMR(DMSO-d6, 400 MHz) 8.34 (s, 1H), 8.09 (d, 1H), 7.85 (d, 1H), 5.38 (s,2H), 3.68 (m, 2H), 3.58 (m, 4H), 3.44 (m, 2H), 2.19 (s, 3H) ppm; MS (ES)expect M+H=389.1, found 389.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(6-methylpyridazin-3-yl)-piperazin-1-yl]-ethanone

Title compound was prepared following protocol D, wherein3-Chloro-6-methylpyridazine was used as the heteroaryl halidecomponent:MS (ES) expect M+H=403.1, found=403.0; HPLC retentiontime=1.68 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B(A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formicacid/99.9% acetonitrile).

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-piperazin-1-yl]-ethanone

Title compound was prepared following protocol D, wherein2-Chloro-4,6-dimethoxytriazine was used as the heteroaryl halidecomponent: MS (ES) expect M+H=450.1, found=450.0; HPLC retentiontime=4.24 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B(A=0.1% formic acid/5% acetonitrile/94.9% water, B 0.08% formicacid/99.9% acetonitrile).

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2-methylsulfanyl-pyrimidin-4-yl)-piperazin-1-yl]-ethanone

Title compound was prepared following protocol D, wherein4-Chloro-2-methylthiopyrrimidine was used as the heteroaryl halidecomponent: ¹H NMR (DMSO-d6, 400 MHz) 8.16 (d, 1H), 6.87 (d, 1H), 5.41(s, 2H), 3.90 (br m, 4H), 3.62 (m, 4H), 2.57 (s, 3H), 2.19 (s, 3H) ppm;MS (ES) expect M+Na=435.1, found 435.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4,6-dimethoxypyrimidin-2-yl)-piperazin-1-yl]-ethanone

Title compound was prepared following protocol D, wherein2-Chloro-4,6-dimethoxypyrrimidine was used as the heteroaryl halidecomponent: MS (ES) expect M+H=449.1, found=449.0; HPLC retentiontime=4.92 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B(A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formicacid/99.9% acetonitrile).

Synthesis of1-[4-(6-Chloro-5-methyl-pyridazin-3-yl)-piperazin-1-yl]-2-(4-chloro-5methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Title compound was prepared following protocol D, wherein3,6-Dichloro-4-methylpyridazine was used as the heteroaryl halidecomponent: MS (ES) expect M+H=437.1, found=437.0; HPLC retentiontime=4.17 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B(A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formicacid/99.9% acetonitrile).

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(5-methoxy-1-H-benzoimidazol-2-yl)-piperazin-1-yl]-ethanone

Title compound was prepared following protocol D, wherein2-Chloro-5-methoxybenzimidazole was used as the heteroaryl halidecomponent: MS (ES) expect M+H=457.1, found=457.0; HPLC retentiontime=2.85 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a4.5 minute gradient of 20% to 95% B with a 1.1 minute wash at 95% B(A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formicacid/99.9% acetonitrile).

Further Functionalization of Arylpiperazine Ring System After its FormalConstruction

Key compounds of the current invention have, in addition to otherselected substituents, a halogen atom at the 2- or 4-position.Approaches to install this are described in the following section.

Functionalization of the aryl ring within the arylpiperazine ring systemcan, in general, take place either before or after introduction of thepiperazine ring, as illustrated in the examples below.

Protocol E: Selected Examples of Halogenation of Aromatic Systems AfterAttachment of the Piperazine Ring System

Synthesis of 1-(4-Bromo-3-methoxy-phenyl)-piperazine hydrochloride

To a solution of 2.33 g (8.8 mmol) of 1-(3-Methoxyphenyl)piperazinedihydrochloride and 756 mg (9.7 mmol) sodium acetate in 70 mL of aceticacid and 15 mL of water at 0° C. was added 1.55 g (9.7 mmol) bromine.After 1 hour, the reaction was concentrated to an oil in vacuo, and theoil was partitioned between ethyl acetate and 1M NaOH. The phases wereseparated, and the ethyl acetate phase was washed once each with waterand brine, dried over Na2SO4, filtered, and the filtrate wasconcentrated to an oil in vacuo. The oil was dissolved in a minimumvolume of methanol, and the solution was acidified with 2M HCl in ether.The product was isolated by filtration. ¹H NMR (D₂O, 400 MHz) 7.36 (d,1H), 6.73 (s, 1H), 6.50 (d, 1H), 3.75 (s, 3H), 3.32 (m, 8H) ppm.

Synthesis of 1-(4-Bromo-3-methyl-phenyl)-piperazine hydrochloride

To a solution of 966 mg (4.0 mmol) of 1-(3-Methylphenyl)piperazinedihydrochloride in 9 mL of acetic acid and 1 mL of water at 0° C. wasadded 640 mg (4.0 mmol) of bromine. After 1 hour, the reaction wasconcentrated to an oil in vacuo, and the oil was partitioned betweenethyl acetate and 1M NaOH. The phases were separated, and the ethylacetate phase was washed once each with water and brine, dried overNa2SO4, filtered, and the filtrate was concentrated to an oil in vacuo.The oil was dissolved in a minimum volume of methanol, and the solutionwas acidified with 2M HCl in ether. The product was isolated byfiltration. ¹H NMR (D₂O, 400 MHz) 7.37 (d, 1H), 6.85 (s, 1H), 6.76 (d,1H), 3.37 (m, 8H), 2.17 (s, 3H) ppm.

Synthesis of 1-(2-Chloro-5-methoxy-phenyl)-piperazine hydrochloride

To a solution of 5.3 g (20 mmol) of 1-(3-Methoxyphenyl)piperazinedihydrochloride in 120 mL of acetic acid and 30 mL of water at 0° C. wasadded 3.3 g (20 mmol) of N-chlorosuccinimide. After 5 hours, thereaction was concentrated to an oil in vacuo, and the oil waspartitioned between ethyl acetate and 1M NaOH. The phases wereseparated, and the ethyl acetate phase was washed once each with waterand brine, dried over Na2SO4, filtered, and the filtrate wasconcentrated to an oil in vacuo. The oil was dissolved in a minimumvolume of methanol, and the solution was acidified with 2M HCl in ether.The product was isolated by filtration. ¹H NMR (D₂O, 400 MHz) 7.28 (d,1H), 6.66 (m, 3H), 3.70 (s, 3H), 3.32 (m, 4H), 3.20 (m, 4H) ppm.

Synthesis of 1-(2,4-Dichloro-5-methoxy-phenyl)-piperazine hydrochloride

To a solution of 530 mg (2.0 mmol) of 1-(3-Methoxyphenyl)piperazinedihydrochloride in 7 mL of acetic acid and 4 mL of water at 0° C. wasadded 700 mg (4.4 mmol) of N-chlorosuccinimide. The reaction was takenout of the ice/water bath after 2 hours, and allowed to stir overnight.After 12 hours, the reaction was concentrated to an oil in vacuo, andthe oil was partitioned between ether and water. The phases wereseparated, the aqueous was basified with 1M NaOH, and was extracted withethyl acetate. The ethyl acetate phase was washed once each with waterand brine, dried over Na2SO4, filtered, and the filtrate wasconcentrated to an oil in vacuo. The oil was dissolved in a minimumvolume of methanol, the solution was acidified with 5M HCl inisopropanol and was diluted with ethyl acetate to effectcrystallization. The product was isolated by filtration. ¹H NMR (D₂O,400 MHz) 7.38 (s, 1H), 6.72 (s, 1H), 3.78 (s, 3H), 3.32 (m, 4H), 3.19(m, 4H) ppm.

Protocol F: Selected Examples of Demethylation/Etherification ofAromatic Precursors for Attachment of the Piperazine Ring System toAccess Key Arylpiperazine Moieties

Synthesis of 3-Bromo-6-chlorophenol

To 50 mL of a 1M solution of boron tribromide in CH2Cl2 at 0° C. wasadded 5.71 g (25.8 mmol) of 5-Bromo-2-chloroanisole. After 2 hours, thereaction was allowed to warm to room temperature. After 5 hours, thesolution was cooled to 0° C., and quenched with methanol. The resultingsolution was partitioned between water and ethyl acetate, and the phaseswere separated. The aqueous phase was back-extracted once with ethylacetate. The combined ethyl acetate phases were diluted with one volumeof ether, and were extracted twice with 1M NaOH. The combined basicaqueous phases were acidified with 12M HCl, and were extracted once withethyl acetate. The final ethyl acetate phase was washed once with brine,dried over MgSO4, filtered, and concentrated to give the phenol as a tansolid. ¹H NMR (DMSO-d6, 400 MHz) 10.66 (s, 1H), 7.27 (d, 1H), 7.08 (s,1H), 6.95 (d, 1H) ppm.

Synthesis of 1-Bromo-3-isopropoxy-4-chlorobenzene

To 1.70 g (6.5 mmol) of triphenylphosphine in 25 mL of CH2Cl2 at 0° C.was added 1.14 g (6.5 mmol) of diethylazodicarboxylate. After 10minutes, 390 mg (6.5 mmol) of isopropanol was added, followed rapidly by1.03 g (5.0 mmol) of 3-Bromo-6-chlorophenol. The reaction was completewithin three hours, and was partitioned between ether and water. Thephases were separated, and the ether phase was diluted with hexanes andwashed twice with 10% aqueous methanol and once with brine. Theether/hexanes phase was dried over Na2SO4, filtered, and concentrated invacuo to yield product as a clear oil.

Protocol F: Additional Examples of Analogous Ring Systems ConstructedUsing Similar Demethylation/Etherification Strategies

Protocol G: General Procedure for the Synthesis of Elaborated ArylBromides from Anilines

Synthesis of 4-Chloro-2-fluoro-1-bromobenzene

Sodium nitrite (2.35 g, 34.13 mmol) solution (40 mL) was added dropwiseto 4-Chloro-2-fluoro aniline (4.5 g, 31 mmol) in 170 mL HBr at −10° C.bath temperature, then the mixture was stirred for 30 min at −10° C.bath temperature. In parallel, copper sulfate (10.22 g, 24.29 mmol) andsodium bromide (3.79 g, 36.8 mmol) were mixed and the reaction mixturewas heated at 60° C. for 30 min. Then sodium sulfite (2.66 g, 21.2 mmol)was added into this copper sulfate reaction mixture and heated for 95°C. for 30 min. The reaction mixture was cooled to room temperature andsolid formed was washed with water to afford white solid cuprousbromide. The diazonium salt was portion wise added into the freshlyprepared cuprous bromide in 40 mL HBr at −10° C. bath temperature andthe reaction mixture was then warmed to room temperature. The reactionmixture was heated at 55° C. for 20 min, cooled and then extracted withethyl acetate three times. The combined organic layer was washed withwater and saturated brine solution, dried over sodium sulfate andconcentrated. The crude material was purified by column chromatography(5:95 ethyl acetate: pet ether) to afford solid product.

Synthesis of (2-Bromo-5-chloro-phenyl)-phenyl-methanone

Sodium nitrite (2.5 g, 36.28 mmol) solution (40 mL) was dropwise addedto the aniline (7 g, 30.2 mmol) in 100 mL HBr at −10° C. bathtemperature, then the mixture was stirred for 30 min at −10° C. bathtemperature to make diazonium salt.

Copper sulfate (10.22 g, 24.29 mmol) and sodium bromide (3.79 g, 36.8mmol) was heated at 60° C. for 30 min. Then sodium sulfite (2.66 g, 21.2mmol) was added into copper sulfate reaction mixture and heated for 95°C. for 30 min. Then the reaction mixture was cooled to rt and solidformed was washed with water to afford white solid cuprous bromide.

Diazonium salt was portion wise added into the freshly prepared cuprousbromide in 40 mL HBr at −10° C. bath temperature and the reactionmixture warmed to room temperature. Then the reaction mixture was heatedat 55° C. for 20 min, cooled to room temperature and extracted withethyl acetate three times. The combined organic layer was washed withwater and saturated brine solution, dried over sodium sulfate andconcentrated. The product was purified by crystallization from DCM/Petether.

Protocol G: Additional Examples of Analogous Ring Systems ConstructedUsing Similar Sandmeyer Type Strategies

These preceding aryl bromides and similar substrates were used in avariety of chemistries, already described, to access arylpiperazinessuch as those listed below.

Synthesis of Heteroaromatic Ring Systems: Core Ring Structure Formation

The types of chemistries which can be applied to synthesize the keyheteroaryl ring structures are listed below. They are separated intoexamples of ring formation and ring functionalization reactions.

Protocol H: Pyrazole Synthesis via Addition of Hydrazines toα,β-acetylenic Ketones

Synthesis of 5-Butyl-3-trifluoromethyl-1H-pyrazole

To a solution of 1-Hexyne (3.37 mL, 29.4 mmol) in THF (30 mL) was addedn-BuLi (2.78 M, 10.2 mL, 29.4 mmol). The solution was stirred at −78° C.for 30 minutes then CF₃CO₂Et (3.5 mL, 29.35 mL) and BF₃-OEt₂ were addedsuccessively. The reaction was further stirred at −78° C. for 2 h andwas quenched with satd. NH₄Cl. It was then warmed up to the roomtemperature. The THF was removed, the residue taken into ether, washedwith saturated brine solution, dried over Na₂SO₄ and reduced. The crudeproduct was then dissolved in benzene (25 mL) and hydrazine (29.4 mmol)was added. The reaction mixture was refluxed overnight, then cooled, thesolvent evaporated, and the residue taken into CH₂Cl₂ (30 mL), washedwith brine, dried over Na₂SO₄ and concentrated to give the titlecompound as colorless oil.

Synthesis of 5-isopropyl-3-trifluoromethyl-1H-pyrazole

Following protocol H, 3-methylbutyne was treated with n-BuLi, CF₃CO₂Etand BF₃-OEt₂ in THF. Reaction with hydrazine in benzene under similarreaction conditions yielded title compound.

Synthesis of 5-propyl-3-trifluoromethyl-1H-pyrazole

Following protocol H, 1-pentyne was treated with n-BuLi, CF₃CO₂Et andBF₃-OEt₂ in THF. Reaction with hydrazine in benzene under similarreaction conditions yielded title compound.

Synthesis of 5-(3-Fluorophenyl)-3-trifluoromethyl-1H-pyrazole

Following protocol H, 1-Ethynyl-3-fluoro-benzene was treated withn-BuLi, CF₃CO₂Et and BF₃-OEt₂ in THF. Reaction with hydrazine in benzeneunder similar reaction conditions yielded title compound.

Protocol I: General Procedure for the Synthesis of Pyrazoles viaCondensation of Hydrazines with β-diketones

Synthesis of 5-ethyl-3-trifluoromethyl-1H-pyrazole

To a solution of 1,1,1-Trifluoro-hexane-2,4-dione (1 g, 5.95 mmol) inabsolute ethanol (10 mL) was added NH₂NH₂.xH₂O drop-wise at 0° C. Thereaction mixture warmed to the room temperature during 1 hour andrefluxed overnight. Ethanol was then evaporated, residue dissolved inethyl acetate (20 mL), washed consecutively with saturated brinesolution and water, dried with Na₂SO₄ and concentrated to give the titlecompound as colorless oil.

Protocol J: Pyrazole Synthesis via Condensation of Hydrazines withβ-Cyanoketones

Synthesis of 5-Phenyl-1-pyrazol-3-amine

2.0 g (0.0138 mol, 1 eq) of benzoylacetonitrile in 40 mL of absoluteethanol was added 2.0 g (0.0399 mol, 3 eq) of anhydrous hydrazine andthe reaction mixture stirred at 85° C. for 2 h. Ethanol was removed at50° C. under vacuum. 5-Phenyl-1-pyrazol-3-amine, obtained as a yellowsolid, was washed with pet ether (100 mL) and dried under vacuum.

Synthesis of Functionalized Heteroaryl Ring Systems

Chlorination or Bromination of Pyrazoles

Protocol K: Chlorination of Pyrazoles with NaOCl in Glacial Acetic Acid

Synthesis of 4-Chloro-1H-pyrazole

To a solution of pyrazole (0.5 g, 7.34 mmol) in glacial acetic acid (4mL) was added NaOCl (0.55 g, 7.34 mmol). The reaction mixture was leftat room temperature for 18 h, then neutralized with saturated Na₂CO₃solution, extracted with CH₂Cl₂ (2×25 mL), the combined organic layersevaporated, then diluted with NaOH, and further extracted with CH₂Cl₂(3×20 mL). The organic extracts were combined, dried over Na₂SO₄ andevaporated to give the title compound as a white solid.

Synthesis of 4-Chloro-3-trifluoromethyl-1H-pyrazole

Following protocol K, 3-trifluoromethylpyrazole was treated with glacialacetic acid and NaOCl, yielding title compound.

Synthesis of 4-Chloro-3-methyl-1H-pyrazole

Following protocol K, 3-methylpyrazole was treated with glacial aceticacid and NaOCl, yielding title compound.

Synthesis of 4-Chloro-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester

Following protocol K, 5-propyl-1H-pyrazole-3-carboxylic acid ethyl esterwas treated with glacial acetic acid and NaOCl under similar reactionconditions, yieliding the title compound.

Protocol L: Chlorination or Bromination of Pyrazoles withN-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS)

Synthesis of 4-Chloro-3-methyl-5-trifluoromethyl-1H-pyrazole

3-methyl-5-trifluoromethylpyrazole was taken into dry DMF (20 mL) andN-chloro succinimide (1.78 g) was added in portions. The mixture wasthen heated at 70° C. for 22 h, cooled to room temperature, and thenwater (100 mL) was added and the mixture extracted with ethyl acetate(4×25 mL). The organic layer was washed with water and brine and driedwith Na₂SO₄. Evaporation of the solvent afforded the title compound.

Syntheses of 4-Chloro-5-thiophen-2-yl-2H-pyrazole-3-carboxylic acidethyl ester

Pyrazole(1 eq) in DMF (0.14M Solution) was treated with NCS (1.5 eq.) inportions, and when all the NCS was dissolved in the reaction mixture, itwas then heated at 70° C. overnight. The reaction mixture was thencooled to rt and quenched with water, extracted with ethyl acetate anddried in MgSO₄. Two products were isolated, including the title compound

Synthesis of 4-Chloro-3,5-diisopropyl-pyrazole

Following protocol L, a the solution of 3,5-diisopropyl-pyrazole (0.5 g,3.57 mmol) in DMF (10 mL) was added NCS (0.72 g, 5.3 mmol) in portionsunder vigorous stirring. The reaction mixture was then heated at 80° C.for 14 h and then the reaction was quenched with water. It was thenextracted with ethyl acetate (2×30 mL). The combined organics werewashed with brine. The organic extracts were combined and dried withNa₂SO₄ and finally evaporated to give the title compound as colorlessoil.

Synthesis of 4-Chloro-3-thiophen-2-yl-1H-pyrazole

Following protocol L, 3-thiophen-2-yl-1H-pyrazole was treated with NCSin DMF., to yield title compound.

Synthesis of 5-tert-Butyl-4-chloro-3-trifluoromethyl-1H-pyrazole

Following protocol L, 5-tert-butyl-3-trifluoromethyl-1H-pyrazole wastreated with NCS in DMF to yield title compound.

Synthesis of 4-Chloro-3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester

Following protocol L, 3-methyl-2H-pyrazole-5-carboxylic acid ethyl esterwas treated with NCS in DMF to yield the title compound.

Synthesis of 4-Chloro-3-thiophen-2-yl-1H-pyrazole-5-carboxylic acidethyl ester

Following protocol L, 3-Thiophen-2-yl-1H-pyrazole-5-carboxylic acidethyl ester was treated with NCS in DMF to yield the title compound.

Synthesis of4-Chloro-5-(5-chloro-thiophen-2-yl)-2H-pyrazole-3-carboxylic acid ethylester

Following protocol L, 3-Thiophen-2-yl-1H-pyrazole-5-carboxylic acidethyl ester was treated with NCS in DMF under to yield the titlecompound.

Synthesis of 4-Chloro-3-(4-fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole

Following protocol L, 3-(4-fluoro-phenyl)-5-methylsulfanyl-1H-pyrazolewas treated with NCS in to yield the title compound.

Synthesis of 5-Butyl-4-chloro-3-trifluoromethyl-1H-pyrazole

Following protocol L, 5-butyl-3-trifluoromethyl-1H-pyrazole was treatedwith NCS in DMF to yield the title compound.

Synthesis of 4-Chloro-5-phenyl-1-pyrazol-3-amine

Following protocol L, to 0.5 g (0.0031 mol, 1 eq) of5-phenyl-1-pyrazol-3-amine in 25 mL of dry acetonitrile was added 0.4 g(0.0031 mol, 1 eq) of N-chlorosuccinimide portion wise and the reactionmixture stirred at room temperature for 30 min. The reaction mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas washed with water, brine and concentrated. The product was purifiedby 60–120 silica gel column (1% of methanol in chloroform).

Synthesis of 4-Bromo-5-phenyl-1-pyrazol-3-amine

Following protocol L, to 0.5 g (0.0031 mol, 1 eq) of5-phenyl-1-pyrazol-3-amine in 25 mL of dry acetonitrile was added 0.55 g(0.0031 mol, 1 eq) of N-bromosuccinimide portion wise and the reactionmixture stirred at room temperature for 30 min. The reaction mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas washed with water, brine and concentrated. The product was purifiedby 60–120 silica gel column (1% of methanol in chloroform).

Synthesis of 4-Chloro-5-isopropyl-3-trifluoromethylpyrazole

Following protocol L, to the solution of3-trifluoromethyl-5-isopropyl-pyrazole (0.22 g, 1.23 mmol) in CH₃CN (10mL) was added NCS (0.19 g, 1.43 mmol) in portions with vigorousstirring. The reaction mixture was then heated under reflux for 14 h,cooled and the reaction quenched with saturated NaHCO₃, extracted withmethylene chloride (2×30 mL) and the combined organic extracts waswashed with brine, dried with Na₂SO₄ and evaporated to give the titlecompound as a white solid.

Synthesis of 4-chloro-5-Ethyl-3-trifluoromethyl-1H-pyrazole

Following protocol L, 5-ethyl-3-trifluoromethyl-1H-pyrazole was treatedwith NCS in CH₃CN to yield title compound

Synthesis of 4-chloro-5-propyl-3-trifluoromethyl-1H-pyrazole

Following protocol L, 5-propyl-3-trifluoromethyl-1H-pyrazole was treatedwith NCS in CH₃CN to yield the title compound.

Synthesis of 4-chloro-5-(3-fluorophenyl)-3-trifluoromethyl-1H-pyrazole

Following protocol L, 5-(3-fluorophenyl )-3-trifluoromethyl-1H-pyrazolewas treated with NCS in CH₃CN to yield the title compound.

Synthesis of 4-chloro-3,5-bistrifluoromethyl-1H-pyrazole

Following protocol L, 3,5-bistrifluoromethyl-1H-pyrazole was treatedwith NCS in CH₃CN to yield the title compound.

Synthesis ofN-(4-Chloro-5-methyl-1H-pyrazol-3-yl)-2,2,2-trifluoro-acetamide

Following protocol L,2,2,2-Trifluoro-N-(5-methyl-1H-pyrazol-3-yl)-acetamide was treated withNCS in CH₃CN to yield the title compound.

Protocol M: General Procedure for Reduction of Nitropyrazoles

Synthesis of 3-Heptafluoropropyl-5-methyl-1H-pyrazol-4-ylamine

To a suspension of zinc dust (1.5 g) in glacial acetic acid (10 mL) wasadded drop-wise, a solution of3-Heptafluoropropyl-5-methyl-4-nitro-1H-pyrazole (0.295 g, 1.0 mmol) inglacial acetic acid (5 mL). The reaction mixture was then allowed tostir at room temperature for 14 h. The zinc salts were then removed byfiltration and the residue washed with ethyl acetate. The combinedorganic extract was concentrated in vaccum, re-dissolved in CHCl₃,washed with NaHCO₃, water and brine. Finally the organic layer was driedwith Na₂SO4 and solvent evaporated to give the title compound as whitesolid.

Synthesis of Bromo-pyrazoles for Aryl-aryl Cross Coupling Reactions andfor Metal Mediated Aminations

General Procedure for Trifluoroacetylation of Aminopyrazoles:

Synthesis of 2,2,2-Trifluoro-N-(5-methyl-1H-pyrazol-3-yl)-acetamide

To a solution of 3-amino-5-methylpyrazole (0.97 g, 10 mmol) and Et₃N(1.39 mL, 10 mmol) in dioxane (25 mL) was added Trifluoroaceticanhydride (TFAA) (1.39 mL, 10 mmol) drop-wise at 10° C. The reactionmixture was stirred at that temperature for 1 h then slowly warmed toroom temperature through next 1 h. Once the reaction is over dioxane wasevaporated, residue resolved in water (20 mL), washed with methylenechloride (30 mL). Organic layer was then dried with Na₂SO₄ andconcentrated to give the title compound as white solid.

Protocol N: Functionalization of Alkyl Substituted Heteroaryl RingSystems: Aminomethylation

Synthesis of (5-Bromomethyl-4-chloro-3-methyl-pyrazol-1-yl)-acetic acidethyl ester

Reagents and Conditions: i) BrCH₂CO₂Et/K₂CO₃/CH₃CN; ii) NBS/AIBN/CCl₄

4-Chloro-3-methyl-5-trifluoromethyl-1H-pyrazole, (10 g, 54 mmol) wasdissolved in acetonitrile (100 mL) and potassium carbonate (30 g, 0.215mol) added. After stirring at room temperature for 1 hour, ethylbromoacetate (11 g, 65 mmol) was added. After 14 h at 70° C., themixture was filtered and the filtrate was concentrated to obtain thecrude product, which was re-crystallized from petroleum ether.

This intermediate ester (5 g, 0.019 mol) was taken in CCl₄ (100 mL) andAIBN (0.053 g, 0.33 mmol) was added to it under nitrogen. The mixturewas irradiated with a regular light bulb. The mixture was brought toreflux and then NBS (3.42 g, 0.019 mol), in four portions in 15 minintervals, was added to the mixture. After complete addition the mixturewas left refluxing under the influence of light for 3 h. The reactionmixture was then filtered and the filtrate was washed with water andbrine. Drying the organic layer (Na₂SO₄) followed by evaporation of thesolvent afforded(5-Bromomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acidethyl ester.

Protocol O: Synthesis of(5-Azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)acetic acid

To 4.6 g (13.2 mmol) of(5-Bromomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)acetic acid ethylester dissolved in 40 mL of anhydrous dimethylformamide was added 1.03 g(15.8 mmol) of sodium azide. After stirring for 12 hours, the solutionwas partitioned between ethyl acetate and water. The phases wereseparated, the aqueous phase was back-extracted with ethyl acetate andthe combined ethyl acetate phases were washed with water and brine,dried over Na2SO4, filtered, and concentrated in vacuo to yield anorange oil.

The oil was dissolved in 25 mL of tetrahydrofuran, 25 mL of 1M NaOH wasadded, and the mixture was stirred vigorously for three hours. Thetetrahydrofuran was then removed in vacuo, and the aqueous solution waswashed once with ether. The aquous phase was then acidified with 1M HCl,and extracted twice with ethyl acetate. The combined ethyl acetatephases were washed with brine, dried over Na2SO4, filtered, andconcentrated to yield the title compounds as an orange solid.

Protocol P (vide infra): Synthesis of2-(5-Azidomethyl-4-chloro-3-trifluromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl]-ethanone

To 2.71 g (13.7 mmol) of 1-(4-Chlorophenyl)piperazine and 3.58 g (12.5mmol) of (5-Azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-aceticacid in 40 mL of anhydrous dimethylformamide was added 4.36 mL (31.2mmol) of triethylamine. The solution was cooled to 0° C., and 5.21 g(13.7 mmol) of O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) was added. After 2 hours the reaction wasdiluted with two volumes of water, and the solvent was decanted awayfrom the resulting oil. The oil was crystallized by dissolving inmethanol and adding water in small portions. The product was isolated asa white solid by filtration: ¹H NMR (DMSO-d6, 400 MHz) 7.23 (d, 2H),6.97 (d, 2H), 5.48 (s, 2H), 4.62 (s, 2H), 3.60 (m, 4H), 3.24 (m, 2H),3.12 (m, 2H) ppm; MS (ES) M+H expected=462.1, found=462.0.

Protocol Q: Synthesis of2-(5-Aminomethyl-4-chloro-3-trifluromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl]-ethanone

2.85 g (6.2 mmol) of2-(5-Azidomnethyl-4-chloro-3-trifluromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl]-ethanonewas dissolved in 80 mL methanol, and 3.61 g (16.0 mmol) of SnCl2 hydratewas added. After two hours, the reaction was concentrated in vacuo toremove the methanol. The residue was partitioned between 0.5M NaOH andethyl acetate, and the phases were separated. The aqueous phase wasback-extracted once with ethyl acetate. The combined ethyl acetatephases were extracted twice with 1M HCl. The acidic aqueous phase wasbasified with 1M NaOH, and was extracted once with ethyl acetate. Thefinal ethyl acetate phase was washed once with brine, dried over Na2SO4,filtered, and concentrated to an oil. The oil was dissolved in methanol,acidified with 2M HCl in ether, and the product was isolated byfiltration after precipitation: ¹H NMR (DMSO-d6, 400 MHz) 8.58 (s, 3H),7.27 (d, 2H), 7.03 (d, 2H), 5.71 (s, 2H), 4.10 (d, 2H), 3.64 (m, 4H),3.32 (m, 2H), 3.19 (m, 2H) ppm; MS (ES) M+H expected=436.1, found=436.0.

Synthesis of2-(5-N,N-Dimethylaminomethyl-4-chloro-3-trifluromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl]-ethanone

To a solution of 50 mg (0.1 mmol) of2-(5-Aminomethyl-4-chloro-3-trifluromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl]-ethanonehydrochloride and 13 mg (0.20 mmol) sodium cyanoborohydride in 0.7 mLmethanol was added 0.025 mL (0.3 mmol) of 37% aqueous formaldehyde.After stirring for four hours, the reaction was quenched with 0.1 mL 12MHCl. One hour later, the solution was concentrated in vacuo. The residuewas partitioned between water and ether, and the phases were separated.The ether phase was back-extracted once with water. The combined aqueousphases were basified with 1M NaOH, and was extracted once with ethylacetate. The ethyl acetate phase was washed once with brine, dried overNa2SO4, filtered, and concentrated to an oil. The oil was dissolved inmethanol, acidified with 2M HCl in ether, and the product was isolatedas a white solid by filtatration: ¹H NMR (DMSO-d6, 400 MHz) 11.07 (br,1H), 7.26 (d, 2H), 7.02 (d, 2H), 5.76 (s, 2H), 4.43 (s, 2H), 3.62 (m,4H), 3.31 (m, 2H), 3.18 (m, 2H), 2.81 (s, 6H) ppm; MS (ES) H) M+Hexpected=464.1, found=464.0.

Protocol R: Urea Derivatization of Aminomethyl Functionality on PyrazoleRing System

Synthesis of1-(4-Chloro-2-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-trifluoromethyl-2H-pyrazol-3-ylmethyl)-urea

To a slurry of 12 mg (0.07 mmol) carbonyldiimidazole and 25 mg (0.05mmol) of2-(5-Aminomethyl-4-chloro-3-trifluromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl]-ethanonehydrochloride in 1.0 mL CH2Cl2 at 0° C. was added 23 mg (0.22 mmol) oftriethylamine dissolved in 0.2 mL CH2Cl2 over five minutes. The mixturewas allowed to warm to room temperature after one hour, and was stirredfor an additional hour.

1.0 mL (0.5 mmol) of 0.5M ammonia in dioxane was added, and theresulting solution was stirred for 12 hours. The solution wasconcentrated in vacuo, and the resulting residue was partitioned betweenethyl acetate and water. The phases were separated, and the aqueousphase was back-extracted once with ethyl acetate. The combined ethylacetate phases were washed once each with water, 1M NaOH, brine, driedover Na2SO4, filtered, and concentrated to a residue. The residue wastriturated with ethyl acetate, and the product was isolated as a whitesolid by filtration: ¹H NMR (DMSO-d6, 400 MHz) 7.23 (d, 2H), 6.96 (d,2H), 6.48 (t, 1H), 5.62 (s, 2H), 5.48 (s, 2H), 4.16 (d, 2H), 3.57 (m,4H), 3.25 (m, 2H), 3.14 (m, 2H) ppm; MS (ES) M+H expected=479.1,found=479.0.

Synthesis of3-(4-Chloro-2-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-trifluoromethyl-2H-pyrazol-3-ylmethyl)-1,1-dimethyl-urea

Title compound was prepared following protocol R, using 2M dimethylaminein tetrahydrofuran as the amine component in the second step, to givethe desired product as a solid: ¹H NMR (DMSO-d6, 400 MHz): 7.23 (d, 2H),6.96 (d, 2H), 6.81 (t, 1H), 5.43 (s, 2H), 4.21 (d, 2H), 3.56 (m, 4H),3.22 (m, 2H), 3.13 (m, 2H), 2.73 (s, 3H) ppm; MS (ES) M+Hexpected=507.1, found=507.1.

Synthesis of1-(4-Chloro-2-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-trifluoromethyl-2H-pyrazol-3-ylmethyl)-3-methyl-urea

Title compound was prepared following the protocol R, using 2Mmethylamine in tetrahydrofuran as the amine component in the secondstep, to give the desired product as a solid: ¹H NMR (DMSO-d6, 400 MHz)7.23 (d, 2H), 6.96 (d, 2H), 6.45 (t, 1H), 5.86 (m, 1H), 5.48 (s, 2H),4.18 (d, 2H), 3.58 (m, 4H), 3.31 (s, 3H), 3.25 (m, 2H), 3.13 (m, 2H)ppm; MS (ES) M+H expected=493.1, found=493.0.

Synthesis of3-(4-Chloro-2-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-trifluoromethyl-2H-pyrazol-3-ylmethyl)-1-methoxy-1-methyl-urea

Title compound was prepared following protocol R, using 1MN,O-dimethylhydroxylamine in tetrahydrofuran as the amine component inthe second step, to give the desired product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.63 (t, 1H), 7.23 (d, 2H), 6.96 (d, 2H), 5.42 (s,2H), 4.25 (d, 2H), 3.57 (m, 4H), 3.52 (s, 3H), 3.25 (m, 2H), 3.13 (m,2H), 2.89 (s, 3H) ppm; MS (ES) M+H expected=523.1, found 523.0.

Synthesis of1-(4-Chloro-2-{2-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-trifluoromethyl-2H-pyrazol-3-ylmethyl)-3-ethyl-urea

Title compound was prepared following protocol R, using 2M ethylamine intetrahydrofuran as the amine component in the second step, to give thedesired product as a solid: ¹H NMR (DMSO-d6, 400 MHz) 7.26 (d, 2H), 7.03(d, 2H), 6.95 (br, 11H), 6.47 (br, 1H), 5.49 (s, 2H), 4.17 (s, 1H), 3.61(m, 4H), 3.28 (m, 2H), 3.17 (m, 2H), 2.95 (q, 2H), 0.93 (t, 3H) ppm; MS(ES) M+H expected=507.1, found=507.0

Coupling of Pyrazolyl Systems with Carboxylic Acid Equivalents

The following synthesis is an example of this type of chemistry:additional examples (procedure N) have been described elsewhere in thispatent.

Synthesis of 4-Chloro-3-methyl-5-trifhuoromethylpyrazol-1-yl)-aceticacid

Reagents and Conditions: BrCH₂CO₂Et/K₂CO₃/CH₃CN, then LiOH/THF

4-Chloro-3-methyl-5-trifhuoromethylpyrazole (10 g, 0.0539 mol) was takenin acetonitrile (100 mL) and K₂CO₃ (30 g, 0.213 mol) was added to it.The mixture was stirred at rt for 1 h and ethyl bromoacetate (11 g,0.065 mol) was added slowly to it. The mixture was then stirred for 12 hat 70° C. The mixture was filtered and the filtrate was concentrated toget a crude mixture. This crude product was re-crystallized from petether to obtain the corresponding ester

The ester (14.8 g, 0.0565 mol) was dissolved in THF (100 mL) and asolution of LiOH (6.9 g) in water (50 mL) was added to it. The mixturewas stirred for 10 h at room temperature. Excess THF was evaporatedunder reduced pressure and the aqueous layer was washed with ethylacetate to remove any unhydrolysed material. The aqueous layer was thenacidified with 1.5N HCl and extracted with ethyl acetate. The ethylacetate layer was dried and concentrated to obtain the crude acid. Onre-crystallization from ether/pet, priduct was obtained as whitecrystals.

Couplings of Arylpiperazines with Pyrazolyl-acetic Acid Derivatives

Protocol P: Compounds Prepared by HATU Mediated Coupling:

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2,5-dimethylphenyl)-phenyl)-piperazin-1-yl]-ethanone

To 38 mg (0.20 mmol) of 1-(2,5-Dimethylphenyl)piperazine and 53 mg (0.22mmol) of (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acidin 1.6 mL of anhydrous dimethylformamide was added 62 mg (0.6 mmol) oftriethylamine, followed by 84 mg (0.22 mmol) ofO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU). After 6 hours, the reaction was partitionedbetween ethyl acetate and water, and the phases were separated. Theaqueous phase was back-extracted once with ethyl acetate, and thecombined ethyl acetate phases were washed once each with 0.5M pH=7phosphate buffer, water, 1M NaOH, water, brine. The ethyl acetate phasewas then dried over Na2SO4, filtered, and concentrated to a residue invacuo. The residue was dissolved in a minimum volume of 5M HCl inisopropanol, and was precipitated by diluting the solution with ethylacetate. The product was isolated by filtration to give a white solid:¹H NMR (DMSO-d6, 400 MHz) 7.07 (d 1H), 6.90 (s, 1H), 6.82 (d, 1H), 5.39(s, 2H), 3.66 (m, 4H), 2.98 (m, 2H), 2.89 (m, 2H), 2.26 (s, 3H), 2.24(s, 3H), 2.20 (s, 3H) ppm; MS (ES) M+H expected=415.1, found 415.1.

Examples of Additional Compounds Prepared by HATU Mediated Coupling

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-methoxy-phenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following protocol P, wherein1-(3-methoxyphenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a white solid: ¹H NMR(DMSO-d6, 400 MHz) 7.15 (t, 1H), 6.65 (d, 1H), 6.60 (s, 1H), 6.47 (d,1H), 5.38 (s, 2H), 3.72 (s, 3H), 3.65 (m, 4H), 3.28 (m, 2H), 3.19 (m,2H), 2.18 (s, 3H) ppm; MS (ES) M+H expect=417.1, found=417.1.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-2-(R)-methyl-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Chlorophenyl)-3-(R)-methylpiperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a white solid: ¹H NMR(CDCl₃, 300 MHz) 7.25 (d 2H), 6.83 (d, 2H), 4.91 (m, 3H), 4.28 (m, 1H),3.80–3.10 (m, 4H), 2.86 (m, 1H), 2.71 (m, 1H), 2.29 (s, 3H), 1.40 (m,3H) ppm; MS (ES) expect M+H=435.1, found 435.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-o-tolyl-piperazin-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(2-Methylphenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.14 (m, 2H), 6.98 (m, 2H), 5.37 (s, 2H), 3.60 (m,4H), 2.89 (m, 2H), 2.81 (m, 2H), 2.27 (s, 3H), 2.20 (s, 3H) ppm; MS (ES)M+H expect=401.1, found=401.1.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-2-(S)-methyl-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Chlorophenyl)-3-(S)-methylpiperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(CDCl₃, 300 MHz) 7.25 (d 2H), 6.83 (d, 2H), 4.91 (m, 3H), 4.28 (m, 1H),3.80–3.10 (m, 4H), 2.86 (m, 1H), 2.71 (m, 1H), 2.29 (s, 3H), 1.40 (m,3H) ppm; MS (ES) M+H expected=435.1, found=435.0.

Synthesis of2-(4-Chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(5-fluoro-2-methoxy-phenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(2-Methoxy-5-fluorophenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 6.93 (m, 1H), 6.77 (m, 3H), 5.36 (s, 2H), 3.77 (s,3H), 3.59 (m, 4H), 3.07 (m, 2H), 2.98 (m, 2H), 2.19 (s, 3H) ppm; MS (ES)M+H expect 435.1, found 435.0.

Synthesis of2-{4-chloro-3-methyl-5-trifluoromethyl-pyrazol-1-yl}-1-[4-(3-Methylsulfanyl-phenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(3-Methylthiophenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.21 (t, 1H), 6.98 (s, 1H), 6.91 (d, 1H), 6.81 (d,1H), 5.39 (s, 2H), 3.68 (m, 4H), 3.34 (m, 2H), 3.24 (m, 2H), 2.44 (s,3H), 2.19 (s, 3H) ppm; MS (ES) M+H expect 433.1, found 433.0.

Synthesis of1-[4-(4-Bromo-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Bromophenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.36 (d, 2H), 6.92 (d, 2H), 5.37 (s, 2H), 3.60 (m,4H), 3.24 (m, 2H), 3.14 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+Hexpect=465.0, found=465.0.

Synthesis of2-(4-Chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(2,3-dimethylphenyl)piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(2,3-Dimethylphenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: 1H NMR(DMSO-d6, 400 MHz) 7.04 (t, 1H), 6.99 (m, 2H), 5.38 (s, 2H), 3.64 (m,4H), 2.89 (m, 2H), 2.81 (m, 2H), 2.21 (m, 9H) ppm; MS (ES) M+H expect415.1, found 415.1.

Synthesis of2-(4-Chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(2-chloro-5-methoxy-phenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(2-Chloro-5-methoxyphenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.31 (d, 1H), 6.65 (m, 2H), 5.37 (s, 2H), 3.73 (s,3H), 3.62 (m, 4H), 3.02 (m, 2H), 2.96 (m, 2H), 2.19 (s, 3H) ppm; MS (ES)M+H expect=451.1, found=451.0.

Synthesis of1-[4-(4-Bromo-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Bromo-3-methoxyphenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.34 (d,1H), 6.71 (s, 1H), 6.52 (d, 1H), 5.39 (s,2H), 3.82 (s, 3H), 3.62 (m, 4H), 3.30 (m, 2H), 3.20 (m, 2H), 2.19 (s,3H) ppm; MS (ES) M+H expected=495.0, found=495.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2,4-dichloro-phenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(2,4-Dichlorophenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.56 (s, 1H), 7.36 (d, 1H), 7.15 (d, 1H), 5.37 (s,2H), 3.61 (m, 4H), 3.01 (m, 2H), 2.94 (m, 2H), 2.19 (s, 3H) ppm; MS (ES)M+H expect 455.0, found=454.9.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-methoxy-pyridin-2-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Methoxy-pyridin-2-yl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.92 (d, 1H), 6.67 (s 1H), 6.63 (d, 1H), 5.42 (s,2H), 3.96 (s, 3H), 3.88 (m, 2H), 3.73 (m, 4H), 3.62 (m, 2H), 2.19 (s,3H) ppm; MS (ES) M+H expected=418.1, found=418.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3,4-dimethylphenyl)-piperazin1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(3,4-Dimethylphenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.03 (d, 1H), 6.94 (br s, 1H), 6.84 (br s, 1H), 5.38(s, 2H), 3.68 (m, 4H), 3.25 (m, 2H), 3.15 (m, 2H), 2.18 (s, 6H), 2.14(s, 3H) ppm; MS (ES) M+H expected=415.1, found=415.1.

Synthesis of2-(4-Chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(4-trifluoromethoxy-phenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Trifluoromethoxyphenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.20 (d, 2H), 7.04 (d, 2H), 5.38 (s, 2H), 3.60 (m,4H), 3.27 (m, 2H), 3.17 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+Hexpected=471.1, found=471.0.

Synthesis of2-(4-Chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-[4-(2,4-dichloro-5-methoxy-phenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(2,4-Dichloro-5-methoxyphenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.50 (s, 1H), 6.84 (s, 1H), 5.37 (s, 2H), 3.85 (s,3H), 3.62 (m, 4H), 3.07 (m, 2H), 3.00 (m, 2H), 2.19 (s, 3H) ppm; MS (ES)M+H expected=485.1, found=485.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-nitro-phenyl)-piperazin-1-yl]ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Nitrophenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a yellow solid: ¹HNMR (DMSO-d6, 400 MHz) 8.05 (d, 2H), 7.01 (d, 2H), 5.38 (s, 2H), 3.62(m, 6H), 3.52 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) expect M+H=432.1,found=432.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-2-methoxy-phenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Chloro-2-methoxyphenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.02 (s, 1H), 6.93 (m, 2H), 5.36 (s, 2H), 3.82 (s,3H), 3.60 (m, 4H), 3.03 (m, 2H), 2.95 (m, 2H), 2.19 (s, 3H) ppm; MS (ES)M+H expected=451.1, found=451.0.

Synthesis of1-[4-(4-Bromo-3-methyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Bromo-3-methylphenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.38 (d, 1H), 7.01 (s, 1H), 6.78 (d, 1H), 5.38 (s,2H), 3.60 (m, 4H), 3.26 (m, 2H), 3.16 (m, 2H), 2.28 (s, 3H), 2.19 (s,3H) ppm; MS (ES) M+H expected=479.0, found=478.9.

Synthesis of1-[4-(4-Acetyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Acetyl-phenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.80 (d,1H), 6.98 (d, 2H), 5.38 (s, 2H), 3.61 (m,4H), 3.48 (m, 2H), 3.39 (m, 2H), 2.46 (s, 3H), 2.19 (s, 3H) ppm; MS (ES)M+H expected=429.1, found=429.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3,4-dichlorophenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(3,4-Dichlorophenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.40 (d, 1H), 7.16 (s, 1H), 6.95 (d, 1H), 5.37 (s,2H), 3.59 (m, 4H), 3.31 (m, 2H), 3.21 (m, 2H), 2.18 (s, 3H) ppm; MS (ES)M+H expected=455.0, found=455.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-chlorophenyl)-piperazin-1yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(3-Chlorophenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.23 (t, 1H), 7.19 (s, 1H), 6.90 (d, 1H), 6.79 (d,1H), 5.37 (s, 2H), 3.58 (m, 4H), 3.29 (m, 2H), 3.19 (m, 2H), 2.18 (s,3H) ppm; MS (ES) M+H expected=421.1, found=421.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-m-tolyl-piperazin-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(3-Methylphenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.17 (t, 1H), 6.97 (br, 2H), 6.77 (d, 1H), 5.39 (s,2H), 3.68 (m, 4H), 3.31 (m, 2H), 3.22 (m, 2H), 2.27 (s, 3H), 2.19 (s,3H) ppm; MS (ES) M+H expected=401.1, found=401.1.

Synthesis of1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Chloro-3-methoxyphenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.21 (d, 1H), 6.74 (s,1H), 6.56 (d, 1H), 5.39 (s,2H), 3.82 (s, 3H), 3.63 (m, 4H), 3.30 (m, 2H), 3.19 (m, 2H), 2.19 (s,3H) ppm; MS (ES) M+H expected=451.1, found 451.0.

Synthesis of4-{4-[2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzoicacid methyl ester

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 4-Piperazin-1-yl-benzoic acid methyl ester and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.78 (d, 2H), 6.98 (d, 2H), 5.38 (s, 2H), 3.71 (s,3H), 3.60 (m, 4H), 3.46 (m, 2H), 3.37 (m, 2H), 2.19 (s, 3H) ppm; MS (ES)expect M+H=445.1, found 445.0.

Synthesis of2-(4-Chloro-3,5-dimethyl-pyrazol-1-yl)-1-(4-pyridin-4-yl-piperazin-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-pyridyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 8.28 (d, 2H), 7.18 (d,2H), 5.41 (s, 2H), 3.83 (m,2H),3.72 (m, 4H), 3.63 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+Hexpected=388.1, found=388.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(5-methoxy-2-methyl-phenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(3-Methoxy-5-methylphenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.06 (d, 1H), 6.56 (m, 2H), 5.38 (s, 2H), 3.69 (s,3H), 3.62 (m, 4H), 2.92 (m, 2H), 2.84 (m, 2H), 2.20 (s, 3H) ppm; MS (ES)M+H expected=431.1, found=431.1.

Synthesis of2-(4-Chloro-3-trifluoromethyl-5-methyl-pyrazol-1-yl)-1-(4-phenylpiperazin-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-Phenylpiperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.32 (m 4H), 7.02 (m, 1H), 5.40 (s, 2H), 3.74 (m,4H), 3.39 (m, 2H), 3.29 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) expectM+H=387.1, found 387.1.

Synthesis of1-[4-(4-Chloro-3-ethoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Chloro-3-ethoxyphenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.20 (d, 1H), 6.66 (s, 1H), 6.48 (d, 1H), 5.38 (s,2H), 4.08 (q, 2H), 3.61 (m, 4H), 3.25 (m, 2H), 3.16 (m, 2H), 2.18 (s,3H), 1.33 (t, 3H) ppm; MS (ES) M+H expected=465.1, found 465.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-pyridin-2-yl-piperazin-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(2-Pyridyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 8.11 (d, 1H), 7.53 (t, 1H), 6.85 (d,1H), 6.65 (t,1H), 5.37 (s, 2H), 3.59–3.50 (m, 8H), 2.18 (s, 3H) ppm; MS (ES) M+Hexpected=388.1, found=388.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-p-tolyl-piperazin-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Methylphenyl)piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.20 (m, 4H), 5.40 (s, 2H), 3.79 (m, 4H), 3.37 (m,2H), 3.28 (m, 2H), 2.49 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+Hexpected=401.1, found 401.0.

Synthesis of1-[(4-Methanesulfonyl-phenyl)-piperazine-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Methanesulfonyl-phenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.69 (d, 2H), 7.08 (d,2H), 5.38 (s, 2H), 3.59 (m,4H), 3.49 (m, 2H), 3.38 (m, 2H), 3.09 (s, 3H), 2.19 (s, 3H) ppm; MS (ES)M+H expected=465.1, found=465.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Chlorophenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(CDCl₃, 400 MHz) 7.22 (d, 2H), 6.83 (d, 2H), 4.99 (s, 2H), 3.77 (m, 2H),3.72 (m, 2H), 3.19 (m, 2H), 3.16 (m, 2H), 2.28 (s, 3H) ppm; MS (ES) M+Naexpected=443.0, found 443.0.

Synthsis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-methoxyphenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Methoxyphenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(CDCl₃, 400 MHz) 6.88 (m, 4H), 5.00 (s, 2H), 3.78 (m, 3H), 3.76 (m, 2H),3.70 (m, 2H), 3.08 (m, 4H), 2.30 (s, 3H) ppm; MS (ES) M+Naexpected=439.0, found 439.0.

Synthesis of4-{4-[2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzonitrile

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Cyanophenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(CDCl₃, 400 MHz) 7.44 (d, 2H), 6.77 (d, 2H), 4.90 (s, 2H), 3.67 (m, 4H),3.29 (m, 4H), 2.22 (s, 3H) ppm; MS (ES) M+Na expected=434.0, found434.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2-fluorophenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(2-Fluorophenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(CDCl₃, 400 MHz) 7.02 (m, 4H), 5.00 (s, 2H), 3.80 (m, 2H), 3.70 (m, 2H),3.53 (m, 2H), 3.25 (m, 2H), 2.30 (s, 3H) ppm; MS (ES) M+Naexpected=427.0, found 427.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(2-Methoxyphenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(CDCl₃, 400 MHz) 6.62 (m, 1H), 6.48 (m, 3H), 5.01 (s, 2H), 3.73 (s, 3H),3.61 (m, 4H), 3.43 (m, 2H), 2.31 (s, 3H) ppm; MS (ES) M+Hexpected=439.0, found 439.1.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(3-Trifluoromethylphenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(CDCl₃, 400 MHz) 7.38 (m, 1H), 7.11 (m, 3H), 5.00 (s, 2H), 3.79 (m, 2H),3.73 (m, 2H), 3.27 (m, 2H), 3.23 (m, 2H), 2.30 (s, 3H) ppm; MS (ES) M+Hexpected=455.0, found 455.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(4-pyrimidin-2-yl-piperazin-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(2-Pyrimidinyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: MS (ES) M+Hexpected=389.1, found=389.0; HPLC retention time=3.99 minutes (AgilentZorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a 4.5 minute gradient of 20%to 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formicacid/99.9% acetonitrile).

Synthesis of1-[4-(4-Chloro-3-isopropoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Chloro-3-isopropoxy-phenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.21 (d, 1H), 6.71 (s,1H), 6.53 (d, 1H), 5.38 (s,2H), 4.66 (m, 1H), 3.58 (m, 4H), 3.25 (m, 2H), 3.15 (m, 2H), 2.18 (s,3H), 1.26 (d, 6H) ppm; MS (ES) M+H expected=479.1, found=479.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3,4-difluorophenyl)piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(3,4-Difluorophenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz, not F-decoupled) 7.25 (q, 1H), 7.04 (m, 1H), 6.74 (d,1H), 5.37 (s, 2H), 3.57 (m, 4H), 3.24 (m, 2H), 3.12 (m, 2H), 2.18 (s,3H) ppm; MS (ES) M+H expected=423.1, found 423.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(6-methoxy-pyridin-2-yl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(6-Methoxy-pyridin-2-yl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.45 (t, 1H), 6.34 (d,1H), 6.05 (d, 1H), 5.37 (s,2H), 3.77 (s, 3H), 3.50 (m, 6H), 3.34 (m, 2H), 2.18 (s, 3H) ppm; MS (ES)M+H expected=418.1, found=418.0.

Synthesis of4-{4-[2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-N,N-dimethyl-benzenesulfonamide

Title compound was prepared following the HATU mediated couplingprotocol P, wherein N,N-Dimethyl-4-piperazin-1-yl-benzenesulfonamide and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.54 (d, 2H), 7.08 (d, 2H), 5.38 (s, 2H), 3.62 (m,4H), 3.48 (m, 2H), 3.37 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+Hexpected=494.1, found=494.0.

Synthesis of1-[4-(4-Chloro-3-methyl-phenyl)-piperazin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Chloro-3-methylphenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.25 (d, 1H), 7.05 (s,1H), 6.90 (d, 1H), 5.38 (s,2H), 3.64 (m, 4H), 3.27 (m, 2H), 3.17 (m, 2H), 2.26 (s, 3H), 2.19 (s,3H) ppm; MS (ES) M+H expected=435.1, found=435.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-hydroxyphenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(3-Hydroxyphenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.10 (t, 1H), 6.66 (m,2H), 6.45 (d, 1H), 5.39 (s,2H), 3.74 (m, 4H), 3.33 (br, 2H), 3.24 (br, 2H), 2.19 (s, 3H) ppm; MS(ES) M+H expected=403.1, found 403.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(4-Trifluromethylphenyl)-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.50 (d, 2H), 7.07 (d,2H), 5.38 (s, 2H), 3.60 (m,4H), 3.41 (m, 2H), 3.31 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+Hexpected=455.1, found=455.0.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-(3-methyl-4-m-tolyl-piperazin-1-yl)-ethanone

Title compound was prepared following the HATU mediated couplingprotocol P, wherein 1-(3-Methylphenyl)-2-methyl-piperazine and(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were usedas the coupling components, to give the product as a solid: ¹H NMR(DMSO-d6, 400 MHz) 7.68 (br, 1H), 7.17 (br, 1H), 6.71 (br, 2H), 5.41 (m,2H), 4.08 (m, 4H), 3.70 (m, 2H), 3.50 (br m, 2H), 2.30 (s, 3H), 2.18 (s,3H), 1.01 (m, 3H) ppm; MS (ES) M+H expected=415.1, found=415.1.

Protocol S: Preparation of Chloroacetyl Arylpiperazines

Synthesis of 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

1-(4-Fluorophenyl) piperazine (2.8 mmol) was dissolved in 10 mL ofCH₂Cl₂. Triethylamine (5.5 mmol) was added to it and the reaction wascooled to 0° C. Chloroacetylchloride (4.2 mmol) was added to it slowly,and the reaction was warmed to room temperature overnight. Aftercompletion, the reaction was quenched with brine solution and reactionmixture was extracted with methylene chloride. The combined organicphases were washed with brine and water and dried over magnesiumsulfate. The solvent was evaporated and the compound purified by columnchromatography (hexane/ethyl acetate=1.5/1) to afford the title compoundas a white solid. ¹H NMR (400 MHz, CDCl₃): δ 6.9–7.2 (m, 2H), 6.82–6.92(m, 2H), 4.1 (s, 2H), 6.62–3.8 (m, 4H), 3.46–3.6 (m, 4H). ¹³C NMR (400MHz, CDCl₃): 164, 158, 156.2, 148.5, 118.2, 116.8, 52.6, 52.2, 48, 46,42.1, 40.6.

Synthesis of 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

Protocol S was followed using 1-(4-chloro-phenyl) piperazine, Et₃N,chloroacetyl chloride and methylene chloride. Column chromatographyusing a solvent mixture (hexane/ethyl acetate=1.5/1) afforded the titlecompound as a white solid.

Synthesis of2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

Protocol S was followed using 1-(4-chloro-3-methoxyphenyl) piperazine,Et₃N, chloroacetyl chloride and methylene chloride. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1.5/1)afforded the title compounds as a white solid

Synthesis of2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

Protocol S was followed using 1-(4-bromo-3-methoxyphenyl) piperazine,Et₃N, chloroacetyl chloride and methylene chloride. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1.5/1)afforded the title compounds as a white solid

Synthesis of2-Chloro-1-[4-(4-chloro-phenyl)-2-methyl-(R)-piperazin-1-yl]-ethanone

Protocol S was followed using1-(4-Chloro-phenyl)-3-(R)-methyl-piperazine, Et₃N, chloroacetyl chlorideand methylene chloride. Column chromatography afforded the titlecompound

Synthesis of2-Chloro-1-[4-(4-chloro-phenyl)-2-methyl-(S)-piperazin-1-yl]-ethanone

Protocol S was followed using1-(4-Chloro-phenyl)-3-(S)-methyl-piperazine, Et₃N, chloroacetyl chlorideand methylene chloride. Column chromatography afforded the titlecompound.

Protocol T: K₂CO₃ Mediated Coupling Reaction of ChloroacetylArylpiperazines with Pyrazoles

Synthesis of1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-pyrazol-1-yl-ethanone

Pyrazole (112.33 mg, 1.65 mmol) was dissolved in DMF (10 mL). K₂CO₃(228.05 mg, 1.65 mmol) and2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (300 mg, 1.67mmol) were added to it. The reaction was heated to 80° C. for 14 h.After completion, the reaction was cooled to room temperature, quenchedwith brine and then extracted with ethyl acetate. The organic layer wasfurther washed with water (2×25 mL) and brine (2×25 mL) and dried overmagnesium sulfate. The solvent was removed by rotary evaporation to givethe crude product which was purified by column chromatography on silicagel using a solvent mixture (hexane/ethyl acetate=1/1) to afford thetitle compound as white solid. ¹H NMR (400 MHz, CDCl₃): 7.2–7.58 (d,2H), 6.94–7.2 (t, 2H), 6.84–6.9 (dd, 2H), 6.32–6.36 (t, 1H), 5.6 (s,2H), 3.76–3.82 (m, 2H), 3.68–3.74 (m, 2H), 3.04–3.1 (m, 2H), 3.0–3.04(m, 2H). ¹³C NMR (400 MHz, CDCl₃):165, 158, 146.5, 140, 130, 118.4,118.2, 116, 115.8, 107, 54, 51, 50.8 45.8, 42.8.

Synthesis of2-(4-Chloro-5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanoneand2-(4-Chloro-3-phenyl-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1.5/1)afforded a mixture of the title compounds, both as white solids

¹H NMR (400 MHz, CDCl₃): 7.44–7.54 (m, 5H), 6.94–7.2 (t, 2H), 6.84–6.9(dd, 2H), 4.94 (s, 1H), 3.72–3.8 (m, 2H), 3.5–3.6 (m, 2H), 3.0–3.1 (m,4H). ¹³C NMR (400 MHz, CDCl₃) □163.8, 158, 146.5, 130, 128.6, 128.2,118.2, 114.5, 52, 50, 44.5, 42.

¹H NMR (400 MHz, CDCl₃): 7.82–7.88 (m, 2H), 7.38–7.48 (m, 3H), 6.96–7.04(m, 2H), 6.86–6.94 (m, 2H), 5.2 (s, 1H), 3.76–3.86 (m, 2H), 3.62–3.68(m, 2H), 3.06–3.22 (m, 4H). ¹³C NMR (400 MHz, CDCl₃): 164, 130, 128.4,126, 118, 116.4, 52, 50, 43.8, 41.6.

Synthesis of2-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-thiophen-2-yl-2H-pyrazole-3-carboxylicacid ethyl ester

Protocol T was followed using 5-Thiophen-2-yl-2H-pyrazole-3-carboxylicacid ethyl ester, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1.5/1)afforded the title compound. ¹H NMR (400 MHz, CDCl₃): 7.32–7.36 (m, 1H),7.22–7.26 (m, 1H), 7.08 (s, 1H), 7.02–7.08 (dd, 1H), 6.96–7.2 (m, 2H),6.86–6.92 (m, 2H), 4.3–4.4 (q, 2H), 3.52–3.58 (m, 4H), 3.05–3.25 (m,4H), 1.3–1.42 (m, 3H). 13C NMR (400 MHz, CDCl3): 164, 130, 126.8, 126.4,120, 118.2, 115.4, 62.3, 54, 50.5, 42, 44.5, 14.6.

Synthesis of2-(3-Amino-4-bromo-5-phenyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine,K₂CO₃, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethyl acetate=3/7)afforded the title compound as yellow solid. ¹H NMR (400 MHz, CDCl₃):7.74–7.78 (m, 2H), 7.24–7.36 (m, 3H), 6.86–6.92 (m, 2H), 6.74–6.78 (m,2H), 4.9 (s, 2H), 4.22 (s, 2H), 3.64–3.74 (m, 4H), 2.86–3.04 (m, 4H).¹³C NMR (400 MHz, CDCl₃): 164, 146.2, 144.8, 128, 126.8, 118, 114.8, 60,50.2, 50, 48.8, 46, 42, 20.

Synthesis of2-(3-Amino-4-bromo-5-phenyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine,K₂CO₃, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4)afforded the title compound as white solid. ¹H NMR (400 MHz, CDCl₃):7.7–7.8 (m, 2H), 7.24–7.3 (m, 3H), 6.8–6.92 (m, 2H), 6.74–6.78 (m, 2H),4.9 (s, 2H), 4.2 (s, 2H), 3.6–3.7 (m, 4H), 2.86–3.04 (m, 4H). ¹³C NMR(400 MHz, CDCl₃): 164, 146, 145, 128, 127, 118, 114.8, 60.2, 50.4, 50,48.8, 46, 42, 22.

Synthesis of1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(3-heptafluoropropyl-5-methyl-4-nitro-pyrazol-1-yl)-ethanone

Protocol T was followed using3-Heptafluoropropyl-5-methyl-4-nitro-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=3/7)afforded the title compound as oil. ¹H NMR (400 MHz, CDCl₃): 6.9–7.0 (m,2H), 6.8–6.9 (m, 2H), 5.06–5.14 (d, 2H), 3.6–3.8 (m, 4H), 3.06–3.18 (m,4H), 2.56–2.66 (d, 3H). ¹³C NMR (400 MHz, CDCl₃): 160, 146.2, 144,119.2, 118, 52.2, 50.8, 50.4, 46, 42.2, 12.

Synthesis of1-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-(4-chloro-5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Protocol T was followed using4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=2/3)afforded the title compound as white solid. ¹H NMR (400 MHz, CDCl₃):7.82–7.84 (m, 2H), 7.4–7.48 (m, 3H), 6.9–7.04 (m, 2H), 6.88–6.94 (m,2H), 5.22 (s, 1H), 3.76–3.88(m, 2H), 3.6–3.68 (m, 2H), 3.1–3.22 (m, 4H).¹³C NMR (400 MHz, CDCl₃): 164.2, 130.4, 128, 126, 118.2, 116.4, 52.2,50, 44, 41.8.

Synthesis of1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(4-bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Protocol T was followed using4-Bromo-5-methyl-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=2/3)afforded the title compound as white solid. ¹H NMR (400 MHz, CDCl₃):6.96–7 (m, 2H), 6.84–6.9 (m, 2H), 5 (s, 2H), 3.6–3.8 (m, 4H), 3.02–3.16(m, 4H), 2.3 (s, 3H). ¹³C NMR (400 MHz, CDCl₃): 162.6, 146.5, 142,118.5, 116, 52.2, 50.4, 46, 42.2, 15.

Synthesis of1-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-(4-bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Protocol T was followed using4-Bromo-5-methyl-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=2/3)afforded the title compound as white solid. ¹H NMR (400 MHz, CDCl₃):6.96–7.1 (m, 2H), 6.84–6.89 (m, 2H), 5.2(s, 2H), 3.6.2–3.8 (m, 4H),3.0–3.16 (m, 4H), 2.32 (s, 3H). ¹³C NMR (400 MHz, CDCl₃): 162, 146.4,142.2, 118.5, 116.2, 52, 50.4, 46.2, 42.2, 15.2.

Synthesis of1-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-(3-heptafluoropropyl-5-methyl-4-nitro-pyrazol-1-yl)-ethanone

Protocol T was followed using3-Heptafluoropropyl-5-methyl-4-nitro-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/4,R_(f)=0.81) afforded the title compound as colorless oil. ¹H NMR (400MHz, CDCl₃): δ 6.92–7.02 (m, 2H), 6.82–6.9 (m, 2H), 5.04–5.14 (m, 2H),3.64–3.82 (m, 4H), 3.06–3.18 (m, 4H), 2.6–2.66 (d, 3H). ¹³C NMR (400MHz, CDCl₃): 160.4, 146, 144.2, 119.2, 118.2, 52, 50.8, 50.6, 46, 42,12.2.

Synthesis of1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Protocol T was followed using4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone andDMF. Column chromatography using a solvent mixture (hexane/ethylacetate=2/3) afforded the title compound as a white solid. ¹H NMR (400MHz, CDCl₃): 7.4–7.52 (m, 5H), 7.18–7.22 (d, 1H), 6.44–6.48 (d, 1H),6.36–6.42 (dd, 1H), 4.72 (s, 2H), 3.86 (s, 3H), 3.5–3.78 (m, 4H), 3.1(s, 4H). ¹³C NMR (400 MHz, CDCl₃) 164, 156.2, 150.4, 130.5, 130, 128.5,110, 102.2, 56, 52, 50, 44.8, 42.

Synthesis of1-[4-(4-Bromo-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-3-phenyl-5-trifluoromethyl-pyrazol-1-yl)-ethanone

Protocol T was followed using4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone andDMF. Column chromatography using a solvent mixture (hexane/ethylacetate=2/3) afforded the title compound as a white solid. ¹H NMR (400MHz, CDCl₃): 7.42–7.52 (m, 4H), 7.36–7.38 (d, 1H), 6.42–6.46 (d, 1H),6.34–6.38 (dd, 1H), 4.72 (s, 2H), 3.88 (s, 3H), 3.74–3.78 (m, 2H),3.54–3.58 (m, 2H), 3.12–3.18 (m, 4H). ¹³C NMR (400 MHz, CDCl₃): 164,156.2, 152, 132.6, 130.2, 130, 128.8, 110, 102.2, 56, 52, 50, 44.8, 42.

Synthesis of1-[4-(4-Chloro-3-methoxy-piperazin-1-yl]-2-(4-bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Protocol T was followed using4-Bromo-5-methyl-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone andDMF. Column chromatography using a solvent mixture (hexane/ethylacetate=1/4) afforded the title compound as white solid. ¹H NMR (400MHz, CDCl₃): 7.18–7.22 (d, 1H), 6.44–6.48 (d, 1H), 6.36–6.42 (dd, 1H),5.0 (s, 2H), 3.6.2–3.8 (m, 4H), 3.1–3.2 (m, 4H), 2.3 (s, 3H). ¹³C NMR(400 MHz, CDCl₃): 162, 146.6, 142.2, 118.8, 116, 52.2, 50.4, 46.2, 42.2,15.2.

Synthesis of2-(3-Amino-4-bromo-5-phenyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine,K₂CO₃,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone andDMF. Column chromatography using a solvent mixture (hexane/ethylacetate=1/4) afforded the title compound as white solid. ¹H NMR (400MHz, CDCl₃): 7.78–7.84 (d, 2H), 7.32–7.42 (m, 3H), 7.18–7.22 (d, 1H),6.44–6.48 (d, 1H), 6.36–6.42 (dd, 1H), 4.94 (s, 2H), 4.28 (s, 2H), 3.88(s, 3H), 3.76–3.86 (m, 4H), 3.12–3.18 (m, 4H). ¹³C NMR (400 MHz, CDCl₃):164.6, 154.8, 150.2, 144.6, 130, 128.2, 128, 126.4, 109.2, 102, 56, 51,50, 49.6, 45.6, 42.

Synthesis of2-(3-Amino-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxyphenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazol-3-ylamine,K₂CO₃,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone andDMF. Column chromatography using a solvent mixture (hexane/ethylacetate=1/4) afforded the title compound as colorless oil. ¹H NMR (400MHz, CDCl₃): 7.18–7.22 (d, 1H), 6.44–6.48 (d, 1H), 6.36–6.42 (dd, 1H),5.0 (s, 2H), 4.24 (s, 2H), 2.4 (s, 3H), 3.76–3.86 (m, 4H), 3.12–3.18 (m,4H). ¹³C NMR (400 MHz, CDCl₃): 164.6, 154.8, 144.6, 130.2, 130, 128.8,109.2, 102, 56, 51, 49.6, 45.6, 42.

Synthesis of1-[4-(4-Bromo-3-methoxy-piperazin-1-yl]-2-(4-bromo-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Protocol T was followed using4-Bromo-5-methyl-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone andDMF. Column chromatography using a solvent mixture (hexane/ethylacetate=1/4) afforded the title compound as white solid. ¹H NMR (400MHz, CDCl₃): 7.38–7.4 (d, 1H), 6.44–6.46 (d, 1H), 6.26–6.4 (dd, 2H), 5.0(s, 2H), 3.88 (s, 3H), 3.68–3.8 (m, 4H), 3.14–3.22 (m, 4H), 2.3 (s, 3H).¹³C NMR (400 MHz, CDCl₃): 164.4, 158, 152.2, 144, 134, 110, 102.2, 56.6,54.2, 50, 48.8, 46, 42.2, 12.

Synthesis of1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(3-thiophen-2-yl-pyrazol-1-yl)-ethanone

Protocol T was followed using 3-(2-thienyl)pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃);7.48–7.52 (d, 1H), 7.24–7.28 (dd, 1H), 7.14–7.2 (dd, 1H), 6.98–7.2 (m,1H), 6.88–6.96 (m, 2H), 6.78–6.84 (m, 2H), 6.46–6.52 (d, 1H), 5.0 (s,2H), 3.64–3.8 (m, 4H), 2.94–3.1 (m, 4H). ¹³C NMR (400 MHz, CDCl₃):164.4, 158, 152.2, 144, 134, 132, 126, 124, 123.8, 118, 116, 115.8,102.2, 54, 51.2, 50.8, 45.8, 42.2.

Synthesis of2-(4-Chloro-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 4-Chloro-3-trifluoromethyl-1H-pyrazole,K₂CO₃, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as colorless oil. ¹H NMR (400 MHz, CDCl₃):7.64–7.68 (d, 1H), 6.98–7.4 (m, 2H), 6.86–6.92 (m, 2H), 6.98–7.2 (m,1H), 5.4 (s, 2H), 3.78–3.84 (m, 2H), 3.68–3.92 (m, 2H), 3–3.1 (m, 4H).¹³C NMR (400 MHz, CDCl₃): 164.4, 158, 152.2, 144, 132, 118.2, 116, 54,50.2, 50.0, 46.0, 42.2.

Synthesis of1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(3,4,5-tribromo-pyrazol-1-yl)-ethanone

Protocol T was followed using 3,4,5-Tribromo-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/4)afforded the title compound as white solid. ¹H NMR (400 MHz, CDCl₃):6.96–7.2 (m, 2H), 6.84–6.9 (m, 2H), 5.4 (s, 2H), 3.74–3.8 (m, 2H),3.6–3.68 (m, 2H), 3.04–3.14 (m, 4H). ¹³C NMR (400 MHz, CDCl₃): 164.4,158, 156, 144.2, 128, 118.4, 118.2, 116, 100, 52.8, 50.2, 50.0, 46.0,42.2.

Synthesis of2-(3-tert-Butyl-4-chloro-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluorophenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using5-tert-Butyl-4-chloro-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as white solid. ¹H NMR (400 MHz, CDCl₃):6.94–7.22 (m, 2H), 6.84–6.92 (m, 2H), 5.3 (s, 2H), 3.68–3.8 (m, 2H),3.6–3.68 (m, 2H), 3.04–3.2 (m, 4H), 1.4 (s, 9H). ¹³C NMR (400 MHz,CDCl₃): 164.8, 119, 118.4, 118.2, 116.2, 116, 54, 51, 50.8, 45.4, 42.2,30, 29, 27.

Synthesis of2-[3-(4-Fluoro-phenyl)-5-methylsulfanyl-pyrazol-1-yl]-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=2/3)afforded the title compound as white solid. ¹H NMR (400 MHz, CDCl₃):7.7–7.76 (m, 2H), 6.96–7.1 (m, 4H), 6.88–6.92 (m, 2H), 6.64 (s, 1H), 5.3(s, 2H), 3.7–3.84 (m, 4H), 3.04–3.2 (m, 4H), 2.5 (s, 3H). ¹³C NMR (400MHz, CDCl₃): 164.8, 152, 140, 127.4, 119, 118.4, 118.2, 116.2, 116, 108,52.8, 52, 51.8, 45.4, 42.2, 20.

Synthesis of2-[4-Chloro-5-(4-Fluoro-phenyl)-3-methylsulfanyl-pyrazol-1-yl]-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using4-Chloro-3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=2/3)afforded the title compound as white solid. ¹H NMR (400 MHz, CDCl₃):7.82–7.88 (m, 2H), 7.06–7.12 (m, 2H), 6.96–7.1 (m, 2H), 6.88–6.92 (m,2H), 5.2 (s, 2H), 3.68–3.84 (m, 4H), 3.06–3.18 (m, 4H), 2.4 (s, 3H). ¹³CNMR (400 MHz, CDCl₃): 164.8, 158, 147, 135, 127.4, 127, 119, 112.4,112.2, 110, 108.8, 52.8, 52, 51.8, 45.4, 42.2, 18.6.

Synthesis of2-[4-Chloro-3-(4-Fluoro-phenyl)-5-methylsulfanyl-pyrazol-1-yl]-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using4-Chloro-3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=2/3)afforded the title compound as white solid. ¹H NMR (400 MHz, CDCl₃):7.46–7.5 (m, 2H), 7.12–7.18 (m, 2H), 6.96–7.1 (m, 2H), 6.88–6.92 (m,2H), 4.86 (s, 2H), 3.72–3.78 (m, 2H), 3.56–3.62 (m, 2H), 3.06–3.18 (m,4H), 2.54 (s, 3H).

Synthesis of2-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4-Chloro-3-thiophen-2-yl-2H-pyrazole-5-carboxylicacid ethyl ester

Protocol T was followed using4-Chloro-3-Thiophen-2-yl-2H-pyrazole-5-carboxylic acid ethyl ester,K₂CO₃, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethylacetate=1.5/1:R_(f)=0.62) afforded the title compound. ¹H NMR (400 MHz,CDCl₃): 7.06–7.36 (m, 1H), 6.96–7.2 (m, 3H), 6.84–6.92 (m, 3H), 54.46(s, 2H), 4.3–4.4 (q, 2H), 3.6–3.82 (m, 4H), 3.05–3.25 (m, 4H), 1.3–1.42(m, 3H).

Synthesis of2-(4-Amino-3-heptafluoropropyl-5-methyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using4-Amino-3-heptafluoropropyl-5-methyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/4)afforded the title compound as colorless oil. ¹H NMR (400 MHz, CDCl₃):6.92–7.02 (m, 4H), 5.14 (s, 2H), 3.64–3.82 (m, 4H), 3.6 (s, 2H),3.1–3.22 (m, 4H), 2.16 (s, 3H). ¹³C NMR (400 MHz, CD₆CO): 160.4, 158,146, 144.2, 119.8, 118.2, 52, 50.8, 50.6, 46, 42, 12.2.

Synthesis of2-(5-Butyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 5-n-Butyl-3-trifluoromethyl-1H-pyrazole,K₂CO₃, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4)afforded the title compound as colorless oil. ¹H NMR (400 MHz, CDCl₃):7.18–7.24 (m, 2H), 6.78–6.84 (m, 2H), 6.32 (s, 1H), 5.0 (s, 2H),3.66–3.78 (m, 4H), 3.08–3.18 (m, 4H), 2.58–2.64 (t, 2H), 1.6–1.7 (m,2H), 1.38–1.48 (m, 2H), 0.6–1.0 (t, 3H). ¹³C NMR (400 MHz, CDCl₃):160.4, 150, 148, 142, 130, 126, 119.8, 103.2, 52, 50.8, 50.6, 46, 42,30, 26, 22, 14.

Synthesis of2-(4-Chloro-5-butyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using4-Chloro-5-n-butyl-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/4)afforded the title compound as colorless oil. ¹H NMR (400 MHz, CDCl₃):7.18–7.24 (m, 2H), 6.78–6.84 (m, 2H), 5.0 (s, 2H), 3.66–3.78 (m, 4H),3.08–3.2 (m, 4H), 2.58–2.64 (t, 2H), 1.5–1.54 (m, 2H), 1.38–1.48 (m,2H), 0.6–1.0 (t, 3H). ¹³C NMR (400 MHz, CDCl₃): 160.4, 148, 142, 130,128, 119.8, 52, 50.8, 50.6, 46, 42, 30.4, 26, 23, 14.

Synthesis of2-(3-Amino-4-bromo-5-phenyl-pyrazol-1-yl)-1-[4-(4-bromo-3-methoxyphenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine,K₂CO₃, 2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanoneand DMF. Column chromatography using a solvent mixture (hexane/ethylacetate=1/1.5) afforded the title compound as white solid. ¹H NMR (400MHz, CDCl₃): 7.78–7.84 (d, 2H), 7.32–7.42 (m, 3H), 7.18–7.22 (d, 1H),6.44–6.52 (d, 1H), 6.36–6.42 (dd, 1H), 4.94 (s, 2H), 4.28 (s, 2H), 3.84(s, 3H), 3.76–3.82 (m, 4H), 3.12–3.18 (m, 4H). ¹³C NMR (400 MHz, CDCl₃):164.6, 154.8, 150.2, 144.6, 130, 128.8, 128.6, 126.4, 109.2, 102, 56,51, 50, 49.6, 45.6, 42.

Synthesis of2-(4-Bromopyrazol)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 4-Bromo-1H-pyrazol, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃):7.52–7.58 (d, 1H), 7.48–7.52 (d, 1H), 6.95–7.0 (m, 2H), 6.82–6.92 (dd,2H), 5.00 (s, 2H), 3.72–3.80 (t, 2H), 3.64–3.72 (t, 2H), 3.02–3.12 (m,4H). ¹³C NMR (400 MHz, CDCl₃): 164.6, 158.2, 156.2, 146.6, 141.6, 140.2,130.5, 129.6, 118.2, 118.0, 115.2, 116.4, 94.2, 53.8, 50.8, 50.2, 45.4,42.

Synthesis of2-(4-Iodopyrazol)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 4-Iodo-1H-pyrazol, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃);7.58–7.62 (d, 1H), 7.52 (s, 1H), 6.95–7.1 (m, 2H), 6.84–6.92 (dd, 2H),5.00 (s, 2H), 3.72–3.80 (t, 2H), 3.64–3.72 (t, 2H), 3.02–3.12 (m, 4H).¹³C NMR (400 MHz, CDCl₃): 164.6, 158.2, 156.2, 146.8, 140.8, 140.2,130.5, 129.6, 118.2, 118.0, 115.4, 116.8, 96.0, 53.4, 51.2, 50.2, 45.2,42.

Synthesis of2-(3,5-Diisopropyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 3,5-Diisopropyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as white solid. ¹H NMR (400 MHz, CDCl₃):6.92–7.0 (m, 2H), 6.80–6.88 (dd, 2H), 5.88 (s, 1H), 4.92 (s, 2H),3.70–3.80 (t, 4H), 2.90–3.10 (m, 4H), 1.40–1.60 (m, 12H). ¹³C NMR (400MHz, CDCl₃): 160.6, 158.2, 150.2, 119.2, 118.0, 100.0, 50.8, 50.5, 50.2,45.2, 42, 28.2, 26.0, 22.4.

Synthesis of1-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-trifluoromethyl-1H-pyrazole-4-carboxylicacid ethyl ester

Protocol T was followed using 3-Trifluoromethyl-1H-pyrazole-4-carboxylicacid ethyl ester, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as colorless oil. ¹H NMR (400 MHz, CDCl₃);8.15 (s, 1H), 6.98–7.04 (m, 2H), 6.86–6.92 (m, 2H), 5.1 (s, 2H),4.28–4.38 (q, 2H), 3.78–3.84 (m, 2H), 3.62–3.74 (m, 2H), 3.04–3.2 (m,4H), 1.3–1.4 (t, 3H). ¹³C NMR (400 MHz, CDCl₃): 163.4, 160.5, 159.2,156.2, 147, 137.2, 119, 118.8, 116, 115.8, 61, 54, 50.8, 50.0, 45.0,42.2, 14.2.

Synthesis of1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(4-iodo-3,5-dimethyl-pyrazol-1-yl)-ethanone

Protocol T was followed using 4-Iodo-3,5-dimethyl-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃);6.95–7.1 (m, 2H), 6.84–6.92 (dd, 2H), 5.00 (s, 2H), 3.62–3.82 (m, 4H),3.02–3.12 (m, 4H), 2.22–2.32 (d, 6H). ¹³C NMR (400 MHz, CDCl₃): 165,158.2, 156.2, 150.2, 146.8, 141.8, 118.8, 115.4, 115.2, 52.8, 51.6,50.2, 45.2, 42, 14.8, 12.6.

Synthesis of2-(3-Chloro-indazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 3-Chloro-1H-indazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/4)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃)7.64–7.70 (m, 1H), 7.38–7.48 (m, 2H), 7.18–7.26 (m, 2H), 6.94–7.0 (m,2H), 6.82–6.88 (dd, 2H), 5.2 (s, 2H), 3.72–3.82 (m, 4H), 3.02–3.08 (m,4H). ¹³C NMR (400 MHz, CDCl₃): 165, 158.2, 142.8, 134.8, 128.8, 128.4,122, 121.6, 118.8, 118.6, 115.4, 115.2, 110.6, 110.0, 51.8, 50.6, 50.2,45.2, 42.

Synthesis of2-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-propyl-2H-pyrazole-3-carboxylicacid ethyl ester

Protocol T was followed using 5-Propyl-2H-pyrazole-3-carboxylic acidethyl ester, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃):6.94–7.0 (m, 2H), 6.82–6.90 (dd, 2H), 6.7 (s, 1H), 5.5 (s, 2H),4.26–4.32 (q, 2H), 3.62–3.82 (m, 4H), 3.04–3.18 (m, 4H), 2.58–2.64 (t,2H), 1.64–1.74 (m, 2H), 1.34–1.38 (t, 3H), 0.96–1.0 (t, 3H). ¹³C NMR(400 MHz, CDCl₃): 165, 160, 156.2, 152.4, 146.8, 132.8, 118.2, 118.1,115.8, 115.4, 110.2, 61, 53, 50.6, 50.2, 45, 42, 30, 22.8, 14.2, 14.

Synthesis of2-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3-propyl-2H-pyrazole-5-carboxylicacid ethyl ester

Protocol T was followed using 5-Propyl-2H-pyrazole-3-carboxylic acidethyl ester, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as white solid. ¹H NMR (400 MHz, CDCl₃):6.94–7.0 (m, 2H), 6.82–6.90 (dd, 2H), 6.2 (s, 1H), 5.06 (s, 2H),4.34–4.40 (q, 2H), 3.62–3.8 (m, 4H), 3.02–3.12 (m, 4H), 2.54–2.60 (t,2H), 1.64–1.78 (m, 2H), 1.34–1.38 (t, 3H), 0.98–1.4 (t, 3H). ¹³C NMR(400 MHz, CDCl₃): 165, 160, 156.4, 152.2, 146.6, 132.8, 118.4, 118.2,115.8, 115.4, 113.2, 61, 53, 50.6, 50.2, 45.2, 42, 28, 21.8, 14.2, 14.

Synthesis of2-(3,5-Bis-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 3,5-Bis-trifluoromethyl-1H-pyrazole,K₂CO₃, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃):6.94–7.0 (m, 2H), 6.92 (s, 1H), 6.82–7.90 (dd, 2H), 5.2 (s, 2H),3.72–3.8 (t, 2H), 3.58–3.66 (t, 2H), 3.12–3.18 (t, 2H), 3.02–3.12 (t,2H). ¹³C NMR (400 MHz, CDCl₃): 162.2, 158.2, 156.4, 146.5, 118.4, 116.2,115.8, 113.2, 60.4, 53.2, 50.6, 50.2, 45.2, 42.2, 21.2, 14.2.

Synthesis of1-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazole-3,5-dicarboxylicacid diethyl ester

Protocol T was followed using 1H-Pyrazole-3,5-dicarboxylic acid diethylester, K₂CO₃, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanoneand DMF. Column chromatography using a solvent mixture (hexane/ethylacetate=1/1) afforded the title compound as a white solid. ¹H NMR (400MHz, CDCl₃): 7.38 (s, 1H), 6.94–7.0 (m, 2H), 6.82–7.90 (dd, 2H), 5.54(s, 2H), 4.36–4.42 (q, 2H), 4.26–4.32 (q, 2H), 3.60–3.80 (m, 4H),3.02–3.20 (m, 4H), 1.22–1.42 (m, 6H). ¹³C NMR (400 MHz, CDCl₃): 164.2,162.2, 158.2, 157.4, 156.2, 148.5, 144.4, 134.2, 118.4, 116.2, 115.8,114.2, 62, 61.8, 54.2, 50.6, 50.2, 45.2, 42.2, 14.6, 14.2.

Synthesis of2-(3-Amino-4-t-butyl-pyrazol-1-yl)-1-[4-(4-fluorophenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 5-tert-Butyl-1H-pyrazol-3-ylamine, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethylacetate=3/7:R_(f)=0.49) afforded the title compound as colorless oil. ¹HNMR (400 MHz, CDCl₃): 6.92–7.98 (t, 2H), 6.82–6.88 (dd, 2H), 4.84 (s,2H), 3.95 (s, 2H), 3.70–3.90 (m, 4H), 2.95–3.10 (m, 4H), 1.25 (s, 9H).

Synthesis of2-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-4-chloro-5-propyl-2H-pyrazole-3-carboxylicacid ethyl ester

Protocol T was followed using 4-Chloro-5-Propyl-2H-pyrazole-3-carboxylicacid ethyl ester, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=3/7)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃):6.94–7.0 (m, 2H), 6.82–6.90 (dd, 2H), 5.0 (s, 2H), 4.36–4.40 (q, 2H),3.62–3.82 (m, 4H), 3.04–3.18 (m, 4H), 2.58–2.66(t, 2H), 1.64–1.76 (m,2H), 1.34–1.38 (t, 3H), 0.94–1.0 (t, 3H). ¹³C NMR (400 MHz, CDCl₃): 165,160.2, 156.2, 152.4, 147, 133, 118.4, 118.2, 115.8, 115.4, 112.2, 61,53, 50.6, 50.2, 45, 42, 30, 22.8, 14.4, 14.2.

Synthesis of2-(3-tert-Butyl-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using5-tert-Butyl-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a colorless oil. ¹H NMR (400 MHz, CDCl₃);6.92–7.08 (t, 2H), 6.82–6.88 (dd, 2H), 6.52 (s, 1H), 5.08 (s, 2H),3.70–3.80 (m, 2H), 3.58–3.68 (m, 2H), 3.05–3.15 (m, 4H), 1.3 (s, 9H).¹³C NMR (400 MHz, CDCl₃): 164, 161.2, 158.2, 156.4, 147.2, 118.4, 118.2,115.8, 115.4, 108.2, 54, 50.6, 50.2, 45, 44, 30.

Synthesis of2-(5-Amino-3-furan-2-yl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1yl]-ethanone

Protocol T was followed using 3-Furan-2-yl-2H-pyrazol-5-ylamine, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using 100% ethyl acetate afforded the title compound as awhite solid. ¹H NMR (400 MHz, CD₆CO); 7.48–7.52 (m, 1H), 6.98–7.06 (m,2H), 6.52–6.56 (m, 2H), 6.44–6.48 (m, 2H), 5.74 (s, 1H), 4.98 (s, 2H),3.68–3.88 (m, 4H), 3.12–3.24 (m, 4H). MS (ES) M+H) expected=369.4, found370.1.

Synthesis of1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(4-bromo-3,5-dimethyl-pyrazol-1-yl)-ethanone

Protocol T was followed using 4-Bromo-3,5-dimethyl-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃):6.95–7.1 (m, 2H), 6.84–6.92 (dd, 2H), 4.90 (s, 2H), 3.62–3.82 (m, 4H),3.02–3.12 (m, 4H), 2.24–2.34 (d, 6H). ¹³C NMR (400 MHz, CDCl₃): 165,158.4, 156.6, 150.6, 146.8, 141.4, 119, 115.6, 115.2, 52.6, 51.6, 50.4,45.2, 42.2, 14.8, 12.6.

Synthesis of2-[4-Chloro-3-(5-chloro-thiophen-2-yl)-pyrazol-1-yl]-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using4-Chloro-3-(5-chloro-thiophen-2-yl)-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=2/3)afforded the title compound as yellow solid. ¹H NMR (400 MHz, CDCl₃):7.58 (s, 1H), 7.38–7.42 (d, 1H), 6.94–7.1 (m, 2H), 6.84–6.88 (dd, 2H),4.96 (s, 2H), 3.62–3.81 (m, 4H), 3.02–3.14 (m, 4H). ¹³C NMR (400 MHz,CDCl₃): 165, 158.8, 156.8, 142.4, 131, 126.8, 124.8, 119, 116, 115.6,54, 52, 51.6, 46, 42.6.

Synthesis of4-Chloro-2-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-2H-pyrazole-3-carboxylicacid ethyl ester

Protocol T was followed using 4-Chloro-5-methyl-2H-pyrazole-3-carboxylicacid ethyl ester, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=2/3)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃):6.94–7.1 (m, 2H), 6.84–6.88 (dd, 2H), 5.04 (s, 2H), 4.38–4.44 (q, 2H),3.62–3.80 (m, 4H), 3.02–3.14 (m, 4H), 2.3 (s, 3H), 1.36–1.42 (t, 3H).¹³C NMR (400 MHz, CDCl₃): 182, 165, 119, 116.2, 116, 61.4, 52.3, 51,50.8, 45.8, 42.6, 14.4, 10.

Synthesis of4-Chloro-5-(5-chloro-thiophen-2-yl)-2-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2H-pyrazole-3-carboxylicacid ethyl ester

Protocol T was followed using4-Chloro-5-(5-chloro-thiophen-2-yl)-2H-pyrazole-3-carboxylic acid ethylester, K₂CO₃, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanoneand DMF. Column chromatography using a solvent mixture (hexane/ethylacetate=2/3) afforded the title compound as a yellow solid. ¹H NMR (400MHz, CDCl₃): 7.46–7.48 (m, 1H), 6.94–7.1 (m, 2H), 6.84–6.92 (m, 3H), 5.4(s, 2H), 4.34–4.4 (q, 2H), 3.62–3.81 (m, 4H), 3.04–3.24 (m, 4H),1.36–1.44 (m, 3H). MS (ES) M+H) expected=511.41, found 511.

Synthesis of2-(3-Amino-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazol-3-ylamine,K₂CO₃, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4)afforded the title compound as a colorless oil. ¹H NMR (400 MHz, CDCl₃):7.18–7.22 (d, 1H), 6.78–6.84 (d, 2H), 4.8 (s, 2H), 4.4 (s, 2H),3.72–3.82 (m, 4H), 3.08–3.18 (m, 4H), 2.14 (s, 3H).

Synthesis of1-[4-(4-Bromo-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-phenyl-3-trifluoromethyl-pyrazole-1-yl)-ethanone

Protocol T was followed using4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone andDMF. Column chromatography using a solvent mixture (hexane/ethylacetate=2/3:R_(f)=0.58) afforded the title compound as a white solid. ¹HNMR (400 MHz, CDCl₃): 7.81–7.86 (m, 1H), 7.36–7.44 (m, 4H), 6.42–6.48(d, 1H), 6.34–6.38 (dd, 2H), 5.2 (s, 2H), 3.88 (s, 3H), 3.62–3.82 (m,4H), 3.12–3.22 (m, 4H).

Synthesis of1-[4-(4-Fluorophenyl)-piperazin-1-yl]-2-(3-trifluoromethyl-pyrazol)-ethanone

Protocol T was followed using 3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃):7.54–7.60 (m, 1H), 6.94–7.0 (m, 2H), 6.80–6.88 (m, 2H), 6.52–6.58 (d,1H), 5.2 (s, 2H), 3.72–3.80 (t, 2H), 3.62–3.72 (t, 2H), 3.02–3.12 (m,4H). MS (ES) M+H expected 356.33, found 357.1.

Synthesis of1-[4-(4-Fluorophenyl)-piperazin-1-yl]-2-(3-methyl-pyrazol)-ethanone

Protocol T was followed using 3-methyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃):7.38–7.41 (m, 1H), 6.94–7.0 (m, 2H), 6.80–6.88 (m, 2H), 6.08–6.10 (d,1H), 4.95 (s, 2H), 3.74–3.82 (t, 2H), 3.62–3.72 (t, 2H), 3.0–3.1 (m,4H), 2.28 (s, 3H). MS (ES) M+H expected 302.05, found 303.1.

Synthesis of1-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazole-4-carboxylicacid ethyl ester

Protocol T was followed using 1H-Pyrazole-4-carboxylic acid ethyl ester,K₂CO₃, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃):8.2 (s, 1H), 7.92 (s, 1H), 6.94–7.0 (m, 2H), 6.82–6.88 (m, 2H), 5.0 (s,2H), 4.1–4.2 (q, 2H), 3.74–3.82 (t, 2H), 3.62–3.72 (t, 2H), 3.0–3.12 (m,4H), 1.28–1.42 (t, 3H). MS (ES) M+H expected 360.39, found 361.1.

Synthesis of1-[4-(4-Fluorophenyl)-piperazin-1-yl]-2-(4-methyl-pyrazol)-ethanone

Protocol T was followed using 4-methyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃):7.26–7.32 (m, 1H), 6.94–7.0 (m, 2H), 6.80–6.88 (m, 2H), 5.0 (s, 2H),3.62–3.82 (m, 4H), 3.0–3.1 (m, 4H), 2.1 (s, 3H). MS (ES) M+H expected302.35, found 303.1.

Synthesis of1-[4-(4-Fluorophenyl)-piperazin-1-yl]-2-(3-amino-4-bromopyrazole)-ethanone

Protocol T was followed using 4-bromo-3-aminopyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=3/7)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃):7.23 (s, 1H), 6.94–7.0 (m, 2H), 6.80–6.88 (m, 2H), 4.9 (s, 2H), 4.2 (s,2H), 3.72–3.82 (m, 4H), 3.0–3.14 (m, 4H). MS (ES) M+H expected 382.24,found 382.

Synthesis of1-[4-(4-Fluorophenyl)-piperazin-1-yl]-2-(3-amino-4-cyanopyrazole)-ethanone

Protocol T was followed using 3-amino-4-cyano-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=3/7)afforded the title compound as a solid. ¹H NMR (400 MHz, CDCl₃): 7.48(s, 1H), 6.96–7.2 (m, 2H), 6.86–6.92 (m, 2H), 4.96 (s, 2H), 4.88 (s,2H), 3.78–3.86 (m, 4H), 3.08–3.16 (m, 4H). MS (ES) M+H expected 328.25,found 329.1

Synthesis of3-Amino-5-cyanomethyl-1-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazole-4-carbonitrile

Protocol T was followed using5-amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=3/2)afforded the title compound as white solid. ¹H NMR (400 MHz, CDCl₃):6.96–7.2 (m, 2H), 6.86–6.92 (m, 2H), 5.2 (s, 2H), 4.86 (s, 2H),3.78–3.86 (m, 4H), 3.7 (s, 2H), 3.08–3.16 (m, 4H). MS (ES) M+H expected367.39, found 368.1.

Synthesis of1-[4-(4-Fluorophenyl)-piperazin-1-yl]-2-(4-chloro-pyrazol)-ethanone

Protocol T was followed using 4-chloro-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=3/2)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃):7.54–7.56 (d, 2H), 7.46 (s, 1H), 6.94–7.2 (m, 2H), 6.84–6.88 (m, 2H),4.98 (s, 2H), 3.62–3.82 (m, 4H), 3.0–3.1 (m, 4H). MS (ES) M+H expected322.77, found 323.1

Synthesis of2-(3-Amino-5-methyl-pyrazol-1-yl)-1-[4-(4-fluorophenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 5-methyl-1H-pyrazol-3-ylamine, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/4)afforded the title compound as a colorless oil. ¹H NMR (400 MHz, CDCl₃):7.12–7.18 (m, 3H), 7.0–7.08 (t, 2H), 4.8 (s, 2H), 5.1 (s, 2H), 3.78–3.88(m, 4H), 3.18–3.38 (m, 4H), 2.28 (s, 3H). MS (ES) M+H expected 317.37,found 318.1

Synthesis of3-Amino-1-{2-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-1H-pyrazole-4-carboxylicacid ethyl ester

Protocol T was followed using 3-Amino-5-methyl-1H-pyrazole-4-carboxylicacid ethyl ester, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/4)afforded the title compound as a colorless oil. ¹H NMR (400 MHz, CDCl₃):6.94–7.1 (m, 2H), 6.84–6.88 (m, 2H), 5.52 (s, 2H), 4.78 (s, 2H),4.24–4.32 (q, 2H), 3.74–3.82 (m, 4H), 3.0–3.1 (m, 4H), 2.3 (s, 3H),1.31–1.38 (t, 3H). MS (ES) M+H expected 389.43, found 390.1.

Synthesis of2-(3-Amino-4-chloro-5-methyl-pyrazol-1-yl)-1-[4-(4-fluorophenyl)-piperazin-1-piperazin-1-yl]-ethanone

Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazol-3-ylamine,K₂CO₃, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4)afforded the title compound as colorless oil. ¹H NMR (400 MHz, CDCl₃):7.02–7.08 (m, 2H), 6.94–7.0 (t, 2H), 4.85 (s, 2H), 4.2 (s, 2H),3.80–3.88 (m, 4H), 3.14–3.34 (m, 4H), 2.34 (s, 3H). MS (ES) M+H expected317.37, found 318.1. MS (ES) M+H expected 351.81, found 352.1.

Synthesis of2-(3-Amino-4-bromo-5-methyl-pyrazol-1-yl)-1-[4-(4-fluorophenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 4-Bromo-5-methyl-1H-pyrazol-3-ylamine,K₂CO₃, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.Column chromatography ethyl acetate afforded the title compound as acolorless oil. ¹H NMR (400 MHz, CDCl₃): 6.94–7.02 (m, 2H), 6.82–6.88 (t,2H), 4.84 (s, 2H), 4.1 (s, 2H), 3.72–3.78 (m, 4H), 3.04–3.08 (m, 4H),2.16 (s, 3H). MS (ES) M+H expected 317.37, found 318.1. MS (ES) M+Hexpected 396.27, found 396.

Synthesis of2-(5-tert-Butyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using5-tert-Butyl-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a colorless oil. ¹H NMR (400 MHz, CDCl₃)6.94–7.08 (t, 2H), 6.82–6.88 (dd, 2H), 6.32 (s, 1H), 5.14 (s, 2H),3.62–3.80 (m, 4H), 3.05–3.18 (m, 4H), 1.35 (s, 9H). MS (ES) M+H expected412.43, found 413.1

Synthesis of2-{2-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-methyl-2H-pyrazole-3-carboxylicacid ethyl ester

Protocol T was followed using 5-methyl-2H-pyrazole-3-carboxylic acidethyl ester, K₂CO₃,2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/1)afforded the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃):6.94–7.0 (m, 2H), 6.84–6.88 (dd, 2H), 6.58 (s, 1H), 5.04 (s, 2H),4.3–4.38 (q, 2H), 3.62–3.80 (m, 4H), 3.02–3.14 (m, 4H), 2.3 (s, 3H),1.32–1.38 (t, 3H). ¹³C NMR (400 MHz, CDCl₃): 180, 165, 119, 116.2, 116,109, 61.8, 52, 51.5, 50.8, 45.8, 42.6, 14.4, 10.2.

Synthesis of2-(3,5-Diisopropyl-4-chloro-pyrazol-1-yl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using 3,5-Diisopropyl-4-chloro-1H-pyrazole,K₂CO₃, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1,R_(f)=0.76) afforded the title compound as white solid. MS (ES) M+H)expected=406.9, found 407.1.

Synthesis of2-{2-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-5-thiophen-2-yl-2H-pyrazole-3-carboxylicacid ethyl ester

Protocol T was followed using 5-Thiophen-2-yl-2H-pyrazole-3-carboxylicacid ethyl ester, K₂CO₃,2-Chloro-1-[4-(4-Chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1.5/1)afforded the title compound. ¹H NMR (400 MHz, CDCl₃): 7.34–7.38 (m, 1H),7.24–7.26 (m, 1H), 7.12 (s, 1H), 7.04–7.08 (dd, 1H), 6.96–7.2 (m, 2H),6.88–6.94 (m, 2H), 4.32–4.42 (q, 2H), 3.52–3.58 (m, 4H), 3.05–3.35 (m,4H), 1.32–1.42 (m, 3H). 13C NMR (400 MHz, CDCl3): 164.2, 128, 126.8,126.6, 120.2, 118.4, 115.2, 62.5, 54.2, 50.5, 42.6,44, 14.6.

Synthesis of2-(4-Amino-3-heptafluoropropyl-5-methyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using4-Amino-3-heptafluoropropyl-5-methyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Columnchromatography using a solvent mixture (hexane/ethyl acetate=1/4,R_(f)=0.42) afforded the title compound as colorless oil. ¹H NMR (400MHz, CDCl₃); 6.88–6.94 (d, 2H), 7.22–7.26 (d, 2H), 4.98 (s, 2H),3.64–3.82 (m, 4H), 3.1–3.22 (m, 4H), 2.98(s, 2H), 2.18 (s, 3H). MS (ES)M+H) expected=501.82, found 502.1.

Synthesis of1-[4-(4-Chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-5-ethyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Protocol T was followed using4-Chloro-5-ethyl-3-trifluoromethyl-1-H-pyrazol, K₂CO₃,1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3,R_(f)=0.53) afforded the title compound as white solid. ¹H NMR (400 MHz,CDCl₃); 7.18–7.22 (d, 2H), 6.38–6.48 (m, 2H), 4.98 (s, 2H), 3.86 (s,3H), 3.66–3.76 (m, 4H), 3.1–3.2 (m, 4H), 2.66–2.74 (q, 2H), 1.18–1.28(m, 3H). MS (ES) M+H) expected=464.82, found 465.

Synthesis of2-(4-Chloro-5-isopropyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using4-Chloro-5-isopropyl-3-trifluoromethyl-1-H-pyrazol, K₂CO₃,1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethylacetate=5.5/4.5, R_(f)=0.52) afforded the title compound as white solid.¹H NMR (400 MHz, CDCl₃); 7.19–7.22 (d, 2H), 6.42–6.48 (m, 2H), 5.18 (s,2H), 3.88 (s, 3H), 3.56–3.78 (m, 4H), 3.22–3.44 (m, 4H), 3.04–3.14 (m,1H), 1.44–1.48 (d, 6H). 13C NMR (400 MHz, CDCl3): 164.2, 154.8, 151,130, 109.8, 102, 56.2, 54, 50.5, 50, 45.2, 42.6, 26.2, 22.1

Synthesis of2-(4-Chloro-3-isopropyl-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using4-Chloro-3-isopropyl-5-trifluoromethyl-1-H-pyrazol, K₂CO₃,1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3,R_(f)=0.45) afforded the title compound as white solid. ¹H NMR (400 MHz,CDCl₃); 7.19–7.22 (d, 2H), 6.38–6.48 (m, 2H), 5 (s, 2H), 3.86 (s, 3H),3.62–3.78 (m, 4H), 3.08–3.18 (m, 4H), 2.98–3.04 (m, 1H), 1.35–1.41 (d,6H). 13C NMR (400 MHz, CDCl3): 163.8, 154.8, 150.5, 130, 109.8, 102,56.4, 52.8, 50, 49.8, 45.2, 42.6, 26.8, 20.

Synthesis of2-(4-Chloro-3-n-propyl-5-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone

Protocol T was followed using4-Chloro-3-n-propyl-5-trifluoromethyl-1-H-pyrazol, K₂CO₃,1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF.Column chromatography using a solvent mixture (hexane/ethyl acetate=3/7,R_(f)=0.78) afforded the title compound as white solid. ¹H NMR (400 MHz,CDCl₃); 7.22–7.24 (d, 2H), 6.42–6.48 (m, 2H), 5.7 (s, 2H), 3.8 (s, 3H),3.72–3.78 (m, 4H), 3.22–3.42 (m, 4H), 2.66–2.72 (t, 2H), 1.58–1.68 (m,2H), 0.98–1.02 (t, 3H). 13C NMR (400 MHz, CDCl3): 164, 154.8, 150.5,130, 109.8, 102.2, 56.4, 52.8, 50, 49.8, 45.2, 42.6, 26, 21.8, 14.

Synthesis of1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-bromo-3-phenyl-5-trifluoromethyl-pyrazol-1-yl)-ethanone

Protocol T was followed using4-Bromo-3-phenyl-5-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone andDMF. Column chromatography using a solvent mixture (hexane/ethylacetate=1/1, R_(f)=0.51) afforded the title compound as a white solid.¹H NMR (400 MHz, CDCl₃): 7.42–7.52 (m, 5H), 7.18–7.22 (d, 1H), 6.38–6.42(dd, 1H), 6.46–6.48 (d, 1H), 4.94 (s, 2H), 3.88 (s, 3H), 3.5–3.78 (m,4H), 3.18 (s, 4H).

Synthesis of1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-phenyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone

Protocol T was followed using4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone andDMF. Column chromatography using a solvent mixture (hexane/ethylacetate=2/3, R_(f)=0.92) afforded the title compound as a white solid.¹H NMR (400 MHz, CDCl₃): 7.78–7.84 (m, 2H), 7.36–7.52 (m, 4H), 6.38–6.48(m, 2H), 5.2 (s, 2H), 3.88 (s, 3H), 3.62–3.78 (m, 4H), 3.18–3.26 (s,4H). ¹³C NMR (400 MHz, CDCl₃) 164.4, 156, 150.4, 130.4, 130, 128.6,110.2, 102.4, 56.4, 52, 50.4, 44.6, 42.

Synthesis of1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-3-[3-Fluoro-phenyl]-5-trifluoromethyl-pyrazol-1-yl)-ethanone

Protocol T was followed using4-Chloro-3-[3-Fluorophenyl]-5-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone andDMF. Column chromatography using a solvent mixture (hexane/ethylacetate=2/3, R_(f)=0.51) afforded the title compound as a white solid.¹H NMR (400 MHz, CDCl₃): 7.44–7.52 (m, 1H), 7.18–7.28 (m, 4H), 6.38–6.48(m, 2H), 4.94 (s, 2H), 3.84 (s, 3H), 3.52–3.78 (m, 4H), 3.12 (s, 4H).

Synthesis of1-[4-(4-Chloro-3-methoxyphenyl)-piperazin-1-yl]-2-(4-chloro-5-[3-Fluoro-phenyl]-3-trifluoromethyl-pyrazole-1-yl)-ethanone

Protocol T was followed using4-Chloro-5-[3-Fluorophenyl]-3-trifluoromethyl-1H-pyrazole, K₂CO₃,2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone andDMF. Column chromatography using a solvent mixture (hexane/ethylacetate=2/3, R_(f)=0.59) afforded the title compound as a white solid.¹H NMR (400 MHz, CDCl₃): 7.64–7.68 (d, 1H), 7.56–7.62 (d, 1H), 7.36–7.42(m, 1H), 7.22–7.24 (m, 2H), 7.08–7.12 (m, 1H), 6.42–6.52 (m, 2H), 5.2(s, 2H), 3.9 (s, 3H), 3.62–3.82 (m, 4H), 3.12–3.22 (m, 4H).

Protocol U: for the K₂CO₃ Mediated Coupling Reaction of ChloroacetylSubstituted Arylpiperazines with Novel Heteraryl Ring Systems

Synthesis of1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-[5-nitro-indazol-1-yl]-ethanone

2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (0.834 g, 3.3mmol) was taken in dry DMF (15 mL) and dry potassium carbonate (1.6 g,11.6 mmol) was added to it and the reaction mixture stirred at roomtemperature for 1h under nitrogen. 5-Nitro-1H-indazole (0.5 g, 2.9 mmol)in DMF (2 mL) was then added to the mixture through a syringe. Thereaction was heated at 70° C. for 14 h, cooled and then quenched withwater and extracted with ethyl acetate. Drying of the organic layer withNa₂SO₄ followed by concentration afforded material that on purificationon neutral alumina column (pet ether/ethyl acetate) gave title compoundas a pale yellow solid.

Synthesis of1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-[7-nitro-indazol-1-yl]-ethanone

2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (0.834 g, 3.3mmol) was taken in dry DMF (15 mL) and dry potassium carbonate (1.6 g,11.6 mmol) was added to it and the reaction mixture stirred at roomtemperature for 1 h under nitrogen. 7-Nitro-1H-indazole (0.5 g, 2.9mmol) in DMF (2 mL) was then added to the mixture through a syringe. Thereaction was then heated at 70° C. for 14 h, cooled and then quenchedwith water and extracted with ethyl acetate. Drying of the organic layerwith Na₂SO₄ followed by concentration afforded material that waspurified on neutral alumina column (pet ether/ethyl acetate). Theresulting solid was recrystallized from DCM/pet ether to obtain pureproduct as a pale yellow solid.

Synthesis of2-Benzoimidazol-1-yl-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

Benzimidazole (0.785 g, 0.7 mmol) was taken in dry DMF (15 ml) and drypotassium carbonate (340 mg) and KI (20 mg) was added to it and thereaction mixture stirred at room temperature for 1 h under nitrogen.2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (200 mg, 1.1mmol) in DMF (5 ml) was then added to the mixture through a syringe. Thereaction was then heated at 140° C. for 14 h, cooled and then quenchedwith water and extracted with ethyl acetate. Drying of the organic layerwith Na₂SO₄ followed by concentration gave material that on purificationby flash chromatography (CHCl3/MeOH) afforded pure product: ¹H NMR (300MHz, CDCl₃): δ 8.10–7.65 (m, 4H), 7.26 (d, 2H), 6.83 (d, 2H), 4.99 (s,2H), 3.79–3.66 (m, 4H), 3.14 (br, 4H).

Synthesis of1-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-(2,4-dimethyl-imidazol-1-yl)-ethanone

2,4-dimethylimidazole (0.633 g, 0.7 mmol) was taken up in dry DMF (15ml) and dry potassium carbonate (340 mg) and KI (20 mg) was added andthe reaction mixture was stirred at room temperature for 1 h undernitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (200mg, 1.1 mmol) in DMF (5 ml) was then added to the mixture through asyringe. The reaction was then heated at 140° C. for 14 h, cooled andquenched with water and extracted with ethyl acetate. Drying of theorganic layer with Na₂SO₄ followed by concentration gave material thatwas purified on a silica gel column (CHCl3/MeOH): ¹H NMR (300 MHz,CDCl₃): δ 7.25 (d, 2H), 6.80 (d, 2H), 6.53 (s, 1H), 4.62 (s, 2H), 3.78(br, 2H), 3.59 (br, 2H), 3.21 (br, 4H), 2.31 (s, 3H), 2.17 (s, 1H).

Synthesis of2-(5-Amino-3-methylsulfanyl-[1,2,4]triazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

5-Methylsulfanyl-2H-[1,2,4]triazol-3-ylamine (0.216 g, 1.7 mmol) wastaken in dry DMF (15 ml) and dry potassium carbonate (800 mg) and KI (20mg) was added to it and the reaction mixture stirred at room temperaturefor 1 h under nitrogen.2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (500 mg, 1.8mmol) in DMF (5 ml) was then added to the mixture through a syringe. Thereaction was then heated at 140° C. for 14 h cooled and then quenchedwith water and extracted with ethyl acetate. Drying of the organic layerwith Na₂SO₄ followed by concentration afforded crude product that waspurified by column chromatography (CHCl3/MeOH): ¹H NMR (300 MHz,DMSO-d6): δ 7.24 (d, 2H), 6.98 (d, 2H), 6.24 (s, 2H), 4.84 (s, 2H), 3.57(m, 4H), 3.21 (m, 2H), 3.13 (m, 2H), 2.37 (s, 3H).

Synthesis of2-[5-(2-Bromo-phenyl)-tetrazol-1-yl]-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

5-phenyl-1H-tetrazole (0.1216 g, 0.832 mmol) was taken in dry DMF (15ml) and dry potassium carbonate (400 mg) and KI (20 mg) was added to itand the reaction mixture stirred at room temperature for 1 h undernitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (250mg, 0.92 mmol) in DMF (5 ml) was then added to the mixture through asyringe. The reaction was then heated at 140° C. for 14 h, cooled andquenched with water and extracted with ethyl acetate. Drying of theorganic layer with Na₂SO₄ followed by concentration afforded materialthat was further purified by flash column chromatography (ethylacetate/pet ether): ¹H NMR (300 MHz, CDCl₃): δ 8.17 (br, 2H), 7.49 (br,3H), 7.24 (br, 2H), 6.85 (br, 2H), 5.60 (s, 2H), 3.82 (m, 2H), 3.71 (m,2H), 3.19 (m, 4H).

Synthesis of2-[5-(2-Bromo-phenyl)-tetrazol-1-yl]-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone

5-(2-Bromo-phenyl)-1H-tetrazole (0.374 g, 1.66 mmol) was taken in dryDMF (15 mL) and dry potassium carbonate (800 mg) and KI (20 mg) wasadded to it and stirred at rt for 1 h under nitrogen.2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (500 mg, 1.8mmol) in DMF (5 mL) was then added to the mixture through a syringe. Thereaction was then heated at 140° C. for 14 h, cooled and quenched withwater and extracted with ethyl acetate. Drying of the organic layer withNa₂SO₄ followed by concentration afforded material that was furtherpurified by flash column chromatography (ethyl acetate/pet ether): ¹HNMR (300 MHz, CDCl₃): δ 7.90 (d, 1H), 7.74 (d, 1H), 7.45 (t, 1H), 7.35(t, 1H), 7.25 (d, 2H), 6.87 (d, 2H), 5.65 (s, 2H), 3.84 (m, 2H), 3.73(m, 2H), 3.20 (m, 4H).

Preparation of Compounds with Modified Linker Regions

α-Substituted Acetyl Linkers

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-propan-1-one

1-(4-Fluorophenyl)-piperazine (1 g, 5.5 mmol) dissolved in dry CH₂Cl₂(20 ml) was cooled to 0° C. and triethylamine (1.66 g, 16.5 mmol) wasadded to it. 2-bromopropionyl chloride (1.14 g, 6.6 mol) was addedslowly and the reaction mixture stirred for another 1 h at the sametemperature. The mixture was washed with sodium bicarbonate and brineand dried (Na₂SO₄). Evaporation of the solvent afforded the intermediatealkyl bromide (0.68 g, 3.7 mmol) which was taken into dry DMF (20 ml).Potassium carbonate (2.1 g) was added. After stirring for 1 h at roomtemperature under nitrogen,3-Methyl-4-chloro-5-trifluoromethyl-(1H)-pyrazole (1.3 g, 4.1 mmol) inDMF (5 ml) was then added to the mixture through a syringe. The reactionwas then heated at 70° C. for 14 h, cooled and quenched with water andextracted with ethyl acetate. Drying of the organic layer over Na₂SO₄followed by concentration afforded material that was purified on aneutral alumina column (chloroform/methanol).

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-phenyl-ethanone

To 4-Chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl] phenylaceticacid (0.1 g, 0.00036 mol) and 1-(4-chlorophenyl) piperazine (0.060 g;0.00031 mol) in 20 ml of dry CH₂Cl₂ was added 0.2 ml of triethylamineand the reaction mixture stirred at room temperature for 30 min. TBTU(0.1 g, 0.00031 mol) was then added and the reaction mixture was stirredat room temperature for 17 h. The reaction mixture was diluted with 60ml of CH₂Cl₂ and washed with saturated aqueous NaHCO₃ (2×50 ml), brineand then dried over sodium sulfate. The crude product obtained afterconcentration was purified by column chromatography to give the productas an off white solid: ¹H NMR (CDCl₃, 300 MHz) 7.40–6.61 (m, 10H), 3.99(m, 1H), 3.80 (m, 1H), 3.50–2.81 (m, 6H), 1.90 (s, 3H) ppm; MS (ES) M+Hexpected=497.1, found 497.2.

Synthesis of2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-(3-methoxy-phenyl)-ethanone

AIBN (10 mg) was added to a solution of(3-Methoxy-phenyl)-acetic acidmethyl ester (2 g, 11 mmol) in CC14 (30 ml). The solution was thenheated to reflux and NBS (2.3 g, 13 mmol) was added in portions. Aftercomplete addition the reaction mixture was refluxed for 4 h. Aftercooling, solid residue was filtered off and the filtrate concentrated toyield product Bromo-(3-methoxy-phenyl)-acetic acid methyl ester, thatwas washed repeatedly with pet ether.

4-Chloro-3-methyl-5-trifluoromethyl-1H-pyrazole (610 mg, 3.3 mmol) wastaken into dry CH₃CN (15 ml), dry potassium carbonate (1.15 g) was addedto this and the resulting mixture stirred at room temperature for 1 hunder nitrogen. Bromo-(3-methoxy-phenyl)-acetic acid methyl ester (900mg, 2.8 mmol) in CH3CN (5 ml) was then added to the mixture through asyringe. The reaction was then heated at reflux for 10 h, cooled andthen filtered through a celite filter bed. The filtrate was concentratedto obtain(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-aceticacid ethyl ester that was purified by column chromatography on silica(pet ether/ethyl acetate)

(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-aceticacid methyl ester was then dissolved in THF (20 ml) and LiOH (0.39 g) inwater (5 ml) were added. The mixture was stirred at room temperature for4 h. After this period the THF was completely evaporated from thereaction mixture under vacuum. The remaining aqueous layer was extractedwith ethyl acetate (3×5 ml) and the organic layer was discarded. Theaqueous layer was cooled in ice and neutralized by using concentratedHCl. This neutral aqueous layer was extracted with ethyl acetate (3×10ml), the organic layer dried over Na₂SO₄, concentrated and purified byflash chromatography (CHCl3/MeOH) to yield(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-aceticacid

This compound (90 mg, 0.275 mmol) was taken into dry CH₂Cl₂ (10 ml) andcooled to 0° C. To this cold mixture was first added4-chlorophenyl-piperazine (0.059 g, 0.31 mmol) followed by the additionof T3P (0.35 g, 0.55 mmol, 50% solution in EtOAc). The reaction was leftovernight at room temperature. The mixture was diluted with CH₂Cl₂, andthen washed sequentially with saturated NaHCO3 solution, brine, driedover Na2SO4, and concentrated to afford the crude product. Purificationby column chromatograhpy on neutral alumina yielded2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-2-(3-methoxy-phenyl-ethanone:¹H NMR (300 MHz, CDCl₃): δ 7.37–7.21 (m, 3H), 6.96–6.79 (m, 4H), 6.60(s, 1H), 5.31 (s, 1H), 3.99 (m, (m, 1H), 3.80 (s, 3H), 3.79 (m, 1H),3.46 (m, 2H), 3.24 (m, 1H), 3.13 (m, 2H), 2.91 (m, 1H), 1.95 (s, 3H).

Example 2

This example illustrates the activity associated with representativecompounds of the invention.

-   -   Materials and Methods        A. Cells

CCR1 Expressing Cells

-   -   a. THP-1 Cells

THP-1 cells were obtained from ATCC and cultured as a suspension inRPMI-1640 medium supplemented with 2 mM L-glutamine, 1.5 g/L sodiumbicarbonate, 4.5 g/L glucose, 10 mM HEPES, 1 mM sodium pyruvate, 0.05%2-mercaptoethanol and 10% FBS. Cells were grown under 5% CO₂/95% air,100% humidity at 37° C. and subcultured twice weekly at 1:5 andharvested at 1×10⁶ cells/ml. THP-1 cells express CCR1 and can be used inCCR1 binding and functional assays.

-   -   b. Isolated Human Monocytes

Monocytes were isolated from human buffy coats using the Miltenyi beadisolation system (Miltenyi, Auburn, Calif.). Briefly, following a Ficollgradient separation to isolate peripheral blood mononuclear cells, cellswere washed with PBS and the red blood cells lysed using standardprocedures. Remaining cells were labeled with anti-CD14 antibodiescoupled to magnetic beads (Miltenyi Biotech, Auburn, Calif.). Labeledcells were passed through AutoMACS (Miltenyi, Auburn, Calif.) andpositive fraction collected. Monocytes express CCR1 and can be used inCCR1 binding and functional assays.

B. Assays

Inhibition of CCR1 Ligand Binding

CCR1 expressing cells were centrifuged and resuspended in assay buffer(20 mM HEPES pH 7.1, 140 mM NaCl, 1 mM CaCl₂, 5 mM MgCl₂, and with 0.2%bovine serum albumin) to a concentration of 2.2×10⁵ cells/ml for THP-1cells and 1.1×10⁶ for monocytes. Binding assays were set up as follows.First, 0.09 ml of cells (1×10⁵ THP-1 cells/well or 5×10⁵ monocytes) wasadded to the assay plates containing the compounds, giving a finalconcentration of ˜2–10 μM each compound for screening (or part of a doseresponse for compound IC₅₀ determinations). Then 0.09 ml of ¹²⁵I labeledMIP-1α (obtained from Amersham; Piscataway, N.J.) diluted in assaybuffer to a final concentration of ˜50 μM, yielding ˜30,000 cpm perwell, was added, the plates sealed and incubated for approximately 3hours at 4° C. on a shaker platform. Reactions were aspirated onto GF/Bglass filters pre-soaked in 0.3% polyethyleneimine (PEI) solution, on avacuum cell harvester (Packard Instruments; Meriden, Conn.).Scintillation fluid (50 μl; Microscint 20, Packard Instruments) wasadded to each well, the plates were sealed and radioactivity measured ina Top Count scintillation counter (Packard Instruments). Control wellscontaining either diluent only (for total counts) or excess MIP-1α orMIP-1β (1 μg/ml, for non-specific binding) were used to calculate thepercent of total inhibition for compound. The computer program Prismfrom GraphPad, Inc. (San Diego, Calif.) was used to calculate IC₅₀values. IC₅₀ values are those concentrations required to reduce thebinding of labeled MIP-1α to the receptor by 50%.

Calcium Mobilization

To detect the release of intracellular stores of calcium, cells (THP-1or monocytes) were incubated with 3 μM of INDO-1AM dye (MolecularProbes; Eugene, Oreg.) in cell media for 45 minutes at room temperatureand washed with phosphate buffered saline (PBS). After INDO-1AM loading,the cells were resuspended in flux buffer (Hank's balanced salt solution(HBSS) and 1% FBS). Calcium mobilization was measured using a PhotonTechnology International spectrophotometer (Photon TechnologyInternational; New Jersey) with excitation at 350 nm and dualsimultaneous recording of fluorescence emission at 400 nm and 490 nm.Relative intracellular calcium levels were expressed as the 400 nm/490nm emission ratio. Experiments were performed at 37° C. with constantmixing in cuvettes each containing 10⁶ cells in 2 ml of flux buffer. Thechemokine ligands may be used over a range from 1 to 100 nM. Theemission ratio was plotted over time (typically 2–3 minutes). Candidateligand blocking compounds (up to 10 μM) were added at 10 seconds,followed by chemokines at 60 seconds (i.e., MIP-1α; R&D Systems;Minneapolis, Minn.) and control chemokine (i.e., SDF-1α; R&D Systems;Minneapolis, Minn.) at 150 seconds.

Chemotaxis Assays

Chemotaxis assays were performed using 5 μm pore polycarbonate,polyvinylpyrrolidone-coated filters in 96-well chemotaxis chambers(Neuroprobe; Gaithersburg, Md.) using chemotaxis buffer (Hank's balancedsalt solution (HBSS) and 1% FBS). CCR1 chemokine ligands (i.e, MIP-1α,Leukotactin; R&D Systems; Minneapolis, Minn.) are use to evaluatecompound mediated inhibition of CCR1 mediated migration. Otherchemokines (i.e., SDF-1α; R&D Systems; Minneapolis, Minn.) are used asspecificity controls. The lower chamber was loaded with 29 μl ofchemokine (i.e., 0.1 nM MIP-1α) and varying amounts of compound; the topchamber contained 100,000 THP-1 or monocyte cells in 20 μl. The chamberswere incubated 1–2 hours at 37° C., and the number of cells in the lowerchamber quantified either by direct cell counts in five high poweredfields per well or by the CyQuant assay (Molecular Probes), afluorescent dye method that measures nucleic acid content andmicroscopic observation.

-   -   Identification of Inhibitors of CCR1        A. Assay

To evaluate small organic molecules that prevent the receptor CCR1 frombinding ligand, an assay was employed that detected radioactive ligand(i.e, MIP-1α or leukotactin) binding to cells expressing CCR1 on thecell surface (for example, THP-1 cells or isolated human monocytes). Forcompounds that inhibited binding, whether competitive or not, fewerradioactive counts are observed when compared to uninhibited controls.

THP-1 cells and monocytes lack other chemokine receptors that bind thesame set of chemokine ligands as CCR1 (i.e., MIP-1α, MPIF-1,Leukotactin, etc.). Equal numbers of cells were added to each well inthe plate. The cells were then incubated with radiolabeled MLP-1α.Unbound ligand was removed by washing the cells, and bound ligand wasdetermined by quantifying radioactive counts. Cells that were incubatedwithout any organic compound gave total counts; non-specific binding wasdetermined by incubating the cells with unlabeled ligand and labeledligand. Percent inhibition was determined by the equation:% inhibition=(1−[(sample cpm)−(nonspecific cpm)]/[(totalcpm)−(nonspecific cpm)])×100.B. Inhibitors from a Compound Library Identified Using CCR1 ExpressingCells

In a screen of a set of compounds, the normalized standard deviation was17%, indicating that inhibitory activity of 34% or more was significant;again, a 40% threshold was used. These pooled compound plates yielded 39wells that exhibited greater than 40% inhibition of MIP-1α binding. Whenscreened a second time as pooled compound plates, 14 of these wellsdecreased ligand by greater than 40%. To determine which of thecompounds in each well inhibited CCR1 ligation of MIP-1α, the pools weredeconvoluted by testing each of the compounds individually forinhibitory activity in the assay. Because some compounds may acttogether to inhibit binding and deconvolution assays only testedcompounds individually, compounds that were effective in combination butnot singly were not found in this experiment. Testing the compoundssingly identified inhibitory candidates:

C. Inhibitor from Compound Library Identified Using CCR1-ExpressingCells

CCX-105 was identified from the compound screening effort.

Dose Response Curves

To ascertain a candidate compound's affinity for CCR1 as well as confirmits ability to inhibit ligand binding, inhibitory activity was titeredover a 1×10⁻¹⁰ to 1×10⁻⁴ M range of compound concentrations. In theassay, the amount of compound was varied; while cell number and ligandconcentration were held constant. Compound CCX-105 was titered and foundto be a potent inhibitor of CCR1 specific chemokine binding (see Table,for compound 1.001).

CCR1 Functional Assays

CCR1 is a seven transmembrane, G-protein linked receptor. A hallmark ofsignaling cascades induced by the ligation of some such receptors is thepulse-like release of calcium ions from intracellular stores. Calciummobilization assays were performed to determine if the candidate CCR1inhibitory compounds were able to also block aspects of CCR1 signaling.Candidate compounds able to inhibit ligand binding and signaling with anenhanced specificity over other chemokine and non-chemokine receptorswere desired.

Calcium ion release in response to CCR1 chemokine ligands (i.e., MIP-1α,MPIF-1, Leukotactin, etc.) was measured using the calcium indicatorINDO-1. THP-1 cells or monocytes were loaded with INDO-1/AM and assayedfor calcium release in response to CCR1 chemokine ligand (i.e., MIP-1α)addition. To control for specificity, non-CCR1 ligands, specificallybradykinin, was added, which also signals via a seven transmembranereceptor. Without compound, a pulse of fluorescent signal will be seenupon MIP-1α addition. If a compound specifically inhibits CCR1-MIP-1αsignaling, then little or no signal pulse will be seen upon MIP-1αaddition, but a pulse will be observed upon bradykinin addition.However, if a compound non-specifically inhibits signaling, then nopulse will be seen upon both MIP-1α and bradykinin addition.

As shown below, CCX-105 was able to significantly and specificallyinhibit signaling from CCR1.

TABLE 2 Inhibition of calcium signaling Compound MIP-1α¹ Bradykinin¹Comments CCX-105 − + Specific inhibition ¹+, pulse observed, −, no pulseobserved, n.s., non-specific signal (see main text)

One of the primary functions of chemokines is their ability to mediatethe migration of chemokine receptor-expressing cells, such as whiteblood cells. To confirm that CCX-105 inhibited not only CCR1 specificbinding and signaling (at least as determined by calcium mobilizationassays), but also CCR1 mediated migration, a chemotaxis assay wasemployed. THP-1 myelomonocytic leukemia cells, which resemble monocytes,as wells as freshly isolated monocytes, were used as targets forchemoattraction by CCR1 chemokine ligands (i.e., MIP-1α,CCL15/leukotactin). Cells were place in the top compartment of amicrowell migration chamber, while MIP-1α (or other potent CCR1chemokine ligand) and increasing concentrations of CCX-105 or othercandidate compound was loaded in the lower chamber. In the absence ofinhibitor, cells will migrate to the lower chamber in response to thechemokine agonist; if a compound inhibited CCR1 function, then themajority of cells will remain in the upper chamber. To ascertain acandidate compound's affinity for CCR1 as well as to confirm its abilityto inhibit CCR1 mediated cell migration, inhibitory activity was titeredover a 1×10⁻¹⁰ to 1×10⁻⁴ M range of compound concentrations in thischemotaxis assay. In this assay, the amount of compound was varied;while cell number and chemokine agonist concentrations were heldconstant. After the chemotaxis chambers were incubated 1–2 hours at 37°C., the responding cells in the lower chamber were quantified bylabeling with the CyQuant assay (Molecular Probes), a fluorescent dyemethod that measures nucleic acid content, and by measuring with aSpectrafluor Plus (Tecan). The computer program Prism from GraphPad,Inc. (San Diego, Calif.) was used to calculate IC₅₀ values. IC₅₀ valuesare those compound concentrations required to inhibit the number ofcells responding to a CCR1 agonist by 50%.

In Vivo Efficacy

Rabbit Model of Destructive Joint Inflammation

A study was conducted to evaluate the effects of CCX-105 on inhibitingthe inflammatory response of rabbits to an intra-articular injection ofthe bacterial membrane component lipopolysaccharide (LPS). This studydesign mimics the destructive joint inflammation seen in arthritis.Intra-articular injection of LPS causes an acute inflammatory responsecharacterized by the release of cytokines and chemokines, many of whichhave been identified in rheumatoid arthritic joints. Marked increases inleukocytes occur in synovial fluid and in synovium in response toelevation of these chemotactic mediators. Selective antagonists ofchemokine receptors have shown efficacy in this model (see Podolin, etal., J. Immunol. 169(11):6435–6444 (2002)).

In a rabbit LPS study conducted essentially as described in Podolin, etal. ibid., female New Zealand rabbits (approximately 2 kilograms) weretreated intra-articularly in one knee with LPS (10 ng) together witheither vehicle only (phosphate buffered saline with 1% DMSO) or withaddition of CCX-105 (dose 1=50 μM or dose 2=100 μM) in a total volume of1.0 mL. Sixteen hours after the LPS injection, knees were lavaged andcells counts performed. Beneficial effects of treatment were determinedby histopathologic evaluation of synovial inflammation. The followinginflammation scores were used for the histopathologic evaluation:1—minimal, 2—mild, 3—moderate, 4—moderate-marked. As shown below,CCX-105 was able to significantly and specifically inhibit theinflammatory response in this in vivo assay.

TABLE 3 CCX-105 efficacy in a rabbit model of destructive jointinflammation synovium inflammation score Vehicle 3 CCX-105 (dose 1) 2CCX-105 (dose 2) 1Evaluation of Compound 1.028 in a Rat Model of Collagen InducedArthritis

A 17 day developing type II collagen arthritis study was conducted toevaluate the effects of compound 1.028 on arthritis induced clinicalankle swelling. Rat collagen arthritis is an experimental model ofpolyarthritis that has been widely used for preclinical testing ofnumerous anti-arthritic agents (see Trentham, et al., J. Exp. Med.146(3):857–868 (1977), Bendele, et al., Toxicologic Pathol. 27:134–142(1999), Bendele, et al., Arthritis Rheum. 42:498–506 (1999)). Thehallmarks of this model are reliable onset and progression of robust,easily measurable polyarticular inflammation, marked cartilagedestruction in association with pannus formation and mild to moderatebone resorption and periosteal bone proliferation.

Female Lewis rats (approximately 0.2 kilograms) were anesthetized withisoflurane and injected with Freund's Incomplete Adjuvant containing 2mg/ml bovine type II collagen at the base of the tail and two sites onthe back on days 0 and 6 of this 17 day study. Compound 1.028 was doseddaily in a sub-cutaneous manner from day 0 till day 17 at a dose of 25mg/kg and a volume of 1 ml/kg in the following vehicle (20%N,N-dimethylacetamide, 75% corn oil, 5% Tween-80). Caliper measurementsof the ankle joint diameter were taken, and reducing joint swelling wastaken as a measure of efficacy. As shown below, compound 1.028 was ableto significantly and specifically inhibit the arthritis induced ankleswelling in this in vivo assay.

TABLE 4 Efficacy of compound 1.028 in a rat collagen induced arthritisassay change in joint diameter day9–day17 Vehicle 15.7% +/− 2.0%  Normal  0% +/− 0.3% Compound 1.028 9.1% +/− 1.8%

In the table below, structures and activity are provided forrepresentative compounds described herein. Activity is provided asfollows for either or both of the chemotaxis assay and/or binding assay,described above: +, IC₅₀>12.5 μM; ++, 2500 nM<IC₅₀<12.5 μM; +++, 500nM<IC₅₀<2500 nM; and ++++, IC₅₀<500 nM.

Structure

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A compound of having the formula:

wherein the subscript m is an integer of from 0 to 2; each R¹ is amember selected from the group consisting of C₁₋₄ alkyl and C₁₋₄haloalkyl; R^(2a), R^(2b), R^(2c), R^(2d) and R^(2e) are each membersindependently selected from the group consisting of hydrogen, halogen,—OR^(c), —OC(O)R^(c), —NR^(c)R^(d), —SR^(c), —R^(e), —CN, —NO₂,—CO₂R^(c), —CONR^(c)R^(d), —C(O)R^(c), —OC(O)NR^(c)R^(d),—NR^(d)C(O)R^(c), —NR^(d)C(O)₂R^(e), —NR^(c)—C(O)NR^(c)R^(d),—S(O)R^(e), —S(O)₂R^(e), —NR^(c)S(O)₂R^(e), —S(O)₂NR^(c)R^(d), —N₃,—X²OR^(c), —X²OC(O)R^(c), —X²NR^(c)R^(d), —X²SR^(c), —X²CN, —X²NO₂,—X²CO₂R^(c), —X²CONR^(c)R^(d), —X²C(O)R^(c), —X²OC(O)NR^(c)R^(d),—X²NR^(d)C(O)R^(c), —X²NR^(d)C(O)₂R^(e), —X²NR^(c)C(O)NR^(c)R^(d),—X²S(O)R^(e), —X²S(O)₂R^(e), —X²NR^(c)S(O)₂R^(e), —X²S(O)₂NR^(c)R^(d)and —X²N₃, wherein X² is C₁₋₄ alkylene, and each R^(c) and R^(d) isindependently selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each R^(e) isindependently selected from the group consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl and C₂₋₈ alkynyl, and each ofR^(c), R^(d) and R^(e) is optionally further substituted with from oneto three members selected from the group consisting of OH, O(C₁₋₈alkyl), SH, S(C₁₋₈ alkyl), CN, NO₂, NH₂, NH(C₁₋₈ alkyl) and N(C₁₋₈alkyl)₂; R^(3a), R^(3b) and R^(3c) are each members independentlyselected from the group consisting of hydrogen, halogen, phenyl,thienyl, —OR^(f), —OC(O)R^(f), —NR^(f)R^(g), —SR^(f), —R^(h), —CN, —NO₂,—CO₂R^(f), —CONR^(f)R^(g), —C(O)R^(f), —OC(O)NR^(f)R^(g),—NR^(g)C(O)R^(f), —NR^(g)C(O)₂R^(h), —NR^(f)—C(O)NR^(f)R^(g),—S(O)R^(h), —S(O)₂R^(h), —NR^(f)S(O)₂R^(h), —S(O)₂NR^(f)R^(g),—NR^(f)S(O)₂R^(h), —NR^(f)S(O)₂NR^(f)R^(g), —X³OR^(f), —X³OC(O)R^(f),—X³NR^(f)R^(g), —X³SR^(f), —X³CN, —X³NO₂, —X³CO₂R^(f), —X³CONR^(f)R^(g),—X³C(O)R^(f), —X³OC(O)NR^(f)R^(g), —X³NR^(g)C(O)R^(f),—X³NR^(g)C(O)₂R^(h), —X³NR^(f)—C(O)NR^(f)R^(g), —X³S(O)R^(h),—X³S(O)₂R^(h), —X³NR^(f)S(O)₂R^(h) and —X³S(O)₂NR^(f)R^(g) wherein X³ isC_(1-4 alkylene, each R) ^(f) and R^(g) is independently selected fromhydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyl andC₂₋₈ alkynyl, and each R^(h) is independently selected from the groupconsisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₆ cycloalkyl, C₂₋₈ alkenyland C₂₋₈ alkynyl, and wherein any phenyl or thienyl group present isoptionally substituted with from one to three substitutents selectedfrom the group consisting of halogen, —OR^(f), —NR^(f)R^(g), —R^(h),—CN, —NO₂, —CO₂R^(f), —CONR^(f)R^(g), —C(O)R^(f), —X³OR^(f),—X³NR^(f)R^(g), —X³NR^(f)S(O)₂R^(h) and —X³S(O)₂NR^(f)R^(g); with theproviso that the compound is other than CAS Reg. No. 492422-98-7,1-[[4-bromo-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-(5-chloro-2-methylphenyl)-piperazine;CAS Reg. No. 351986-92-0,1-[[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-(4-fluorophenyl)-piperazine;and CAS Reg. No. 356039-23-1,1-[(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)acetyl]-4-(4-fluorophenyl)-piperazine.2. A compound of claim 1, wherein m is 0 or 1; and at least one ofR^(2a) and R^(2e) is hydrogen.
 3. A compound of claim 2, wherein atleast one of R^(3a), R^(3b) and R^(3c) is selected from the groupconsisting of halogen and C₁₋₄ haloalkyl.
 4. A compound of claim 3,wherein R^(2d) is hydrogen and at least two of R^(3a), R^(3b) and R^(3c)are selected from the group consisting of halogen and C₁₋₄ haloalkyl. 5.A compound of claim 4, wherein R^(2c) is selected from the groupconsisting of F, Cl, Br, CN, NO₂, CO₂CH₃, C(O)CH₃ and S(O)₂CH₃, and eachof R^(3a), R^(3b) and R^(3c) is other than hydrogen.
 6. A compound ofclaim 1, wherein m is 0 or 1; and R^(2a) and R^(2e) are each hydrogen.7. A compound of claim 6, wherein at least one of R^(3a), R^(3b) andR^(3c) is selected from the group consisting of halogen and C₁₋₄haloalkyl.
 8. A compound of claim 7, wherein each of R^(3a), R^(3b) andR^(3c) is other than hydrogen.
 9. A compound of claim 1, wherein m is 0or 1; R^(2b) and R^(2e) are each hydrogen.
 10. A compound of claim 1,having the formula:


11. A compound of claim 10, wherein R^(3c) and R^(3a) are eachindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl and C₃₋₆ cycloalkyl.
 12. A compound of claim 1, having theformula:

wherein R^(2c) is halogen, cyano or nitro; R^(2b) is R^(e) or —OR^(c);R^(3a) is selected from the group consisting of NH₂, CF₃, SCH₃, Ph andthienyl; R^(3b) is chloro or bromo; and R^(3c) is selected from thegroup consisting of C_(1-6 alkyl, C) ₁₋₆ haloalkyl andC_(3-6 cycloalkyl.)
 13. A compound of claim 1, having the formula:

wherein R^(2c) is halogen cyano or nitro; R^(2b) is R^(e) or —OR^(c);R^(3a) is selected from the group consisting of C_(1-6 alkyl, C) ₁₋₆haloalkyl and C_(3-6 cycloalkyl; R) ^(3c) is selected from the groupconsisting of NH₂, CF₃, SCH₃, Ph and thienyl; and R^(3b) is chloro orbromo.
 14. A compound of claim 1, having the formula:

wherein R^(2a) is other than hydrogen; R^(2c) is halogen, cyano ornitro; R^(2d) is R^(e) or —OR^(c); R^(3a) is selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₃₋₆ cycloalkyl; R^(3b) ischloro or bromo; and R^(3c) is selected from the group consisting ofNH₂, CF₃, SCH₃, Ph and thienyl.
 15. A compound of claim 1, having theformula:

wherein R^(2a) is other than hydrogen; R^(2c) is halogen, cyano ornitro; R^(2d) is R^(e) or —OR^(c); R^(3a) is selected from the groupconsisting of NH₂, CF₃, SCH₃, Ph and thienyl; R^(3b) is chloro or bromo;and R^(3c) is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl and C₃₋₆ cycloalkyl.
 16. A compound of claim 9, wherein atleast one of R^(3a), R^(3b) and R^(3c) is selected from the groupconsisting of halogen and C₁₋₄ haloalkyl.
 17. A compound of claim 16,wherein each of R^(3a), R^(3b) and R^(3c) is other than hydrogen.
 18. Apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of claim 1.